| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Departments of Global Clinical Development (E.Mo.), Translational Medicine (W.M.K.), and Biometrics (M.K.), NV Organon (part of Schering-Plough), 5340 BH Oss, The Netherlands; Department of Fertility Control and Hormone Therapy (J.E.), Bayer Schering Pharma AG, 13342 Berlin, Germany; The Sexual Health Clinic (D.A., L.V.), Family Federation of Finland, 00101 Helsinki, Finland; Andrology Unit (H.M.B., H.-P.G.), Department of Urology, Martin Luther University Halle-Wittenberg, 06099 Halle, Germany; Department of Endocrinology (J.B., F.C.W.), Manchester Royal Infirmary, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Neuroendocrinology (P.M.B., A.S.), Royal Free Hospital, Hampstead, London NW3 2PF, United Kingdom; Clinic Obstetrics and Gynecology (A.C., M.C.M.), University of Bologna, S. Orsola Hospital, 40138 Bologna, Italy; Nordica Fertility Clinic (L.G., S.L.), 2400 Copenhagen, Denmark; Dinox GmbH Clinical Research (D.H.-M., C.L.), 10115 Berlin, Germany; Institute of Reproductive and Developmental Biology (I.H.), Imperial College London, London SW7 2AZ United Kingdom; Department of Urology (E.L.K.), Catharina Hospital, 5623 EJ Eindhoven, Netherlands; Department of Urology (E.Me., P.F.A.M.), Radboud University Nijmegen Medical Centre, 6500 HC Nijmegen, Netherlands; Institute of Reproductive Medicine (E.N., M.Z.), University of Muenster, 48149 Muenster, Germany; and Departments of Physiology and Obstetrics and Gynecology (A.P.), University of Turku, FIN-20520 Turku, Finland
Address all correspondence and requests for reprints to: Ellen Mommers, Ph.D., Global Clinical Development Department, Organon, part of Schering-Plough, P.O. Box 20, 5340 BH Oss, The Netherlands. E-mail: ellen.mommers{at}organon.com.
 |
Abstract |
|---|
 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Design and Study Subjects: In this double-blind, multicenter study, we randomly assigned 354 healthy men to receive either a low- or high-release ENG implant sc combined with im TU injections (750 mg every 10 or 12 wk or 1000 mg every 12 wk) or placebo implant and injections. Treatment duration was 42 or 44 wk and posttreatment follow-up at least 24 wk.
Results: Overall, spermatogenesis was suppressed to 1 million/ml or less at wk 16 in 89% of men, with approximately 94% in two high-release ENG groups. Suppression was maintained up to the end of the treatment period in 91% of men. For all men who completed the treatment period, 3% never achieved 1 million/ml or less. Median recovery time to a sperm concentration above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16–18 wk). Treatment was well tolerated. As compared with the placebo group, more men in the active treatment groups reported adverse events such as weight gain, mood changes, acne, sweating, or libido change. For both spermatogenesis suppression and safety, differences were small between the active treatment groups.
Conclusions: The combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.
|
Introduction |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Most male hormonal contraception studies performed to date were small and underpowered, and none has been double blinded and placebo controlled (7). Due to the subjective nature of possible side effects, e.g. on mood or libido, a placebo group is indispensable for a thorough assessment of safety. Furthermore, interlaboratory variation in sperm analysis remains a major concern in multicenter studies, despite the use of the WHO manual for semen analyses (12).
We conducted a large placebo-controlled, double-blind, phase II study in healthy men to assess suppression and recovery of spermatogenesis, using two types of ENG implants combined with three dose regimens of long-acting TU injections. Sperm analysis was performed centrally, using an improved method for low sperm counts (13, 14).
|
Subjects and Methods |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
Men were enrolled at 11 sites in six European countries. Men were eligible for the study if they were between 18 and 45 yr of age; were mentally and physically healthy; had a body mass index between 18 and 32 kg/m2; had two pretreatment semen samples with more than 20 million sperm per milliliter with normal morphology and motility; had normal pretreatment hormone levels of FSH, LH, and testosterone; and were willing to use another reliable form of contraception. The exclusion criteria included history or presence of psychiatric, liver, renal, cardiovascular, or prostatic disease; history or presence of any malignancy, diabetes, or genitourinary infection; prostate-specific antigen (PSA) level more than 2.5 ng/ml; hypertension; and any use of lipid-lowering drugs or drugs known to interfere with the pharmacokinetics of steroids. The study was conducted according to the Declaration of Helsinki and local regulations. Approval for the study was obtained from the institutional review boards and local authorities. All men gave written informed consent.
Intervention
All men received a combination of an implant and four or five injections. Two types of sc implants (length 6 cm, diameter 2.5 mm) were used. The low-release (LR) implant contained 178 mg ENG with an average in vitro release of 146 µg/d in the first 3 months and 106 µg/d in the second half-year. This release rate was comparable with the release rate in the study reported by Brady et al. (9). The high-release (HR) implant contained 144 mg ENG with an average in vitro release of 257 µg/d in the first 3 months and 137 µg/d in the second half-year. The release rate was higher than the LR implant due to differences in the outer skin of the implant. The implant was inserted sc with an applicator on the inside of the upper arm.
Three im TU dose regimens were used: 750 mg in 3 ml every 12 wk (TU1), 750 mg in 3 ml every 10 wk (TU2) or 1000 mg in 4 ml every 12 wk (TU3). A loading TU injection was given at wk 4 or 6 for the 10- or 12-wk regimens, respectively.
Placebo implants and injections were identically administered except that it contained no ENG or TU. Men randomized to the placebo group were equally distributed across the three injection regimens as was done for the active treatment groups.
Study procedures
Eligible men were randomly assigned to receive placebo or one of the six active treatments according to a central randomization schedule prepared by Organon using SAS programming. An equal number of men were assigned to each of the seven treatment groups. Investigators, participants, laboratory staff, and the sponsors were blinded to participants’ treatment assignment. Participants had to use alternative contraceptive methods throughout the trial.
Treatment duration was 42 wk for the 12-wk regimens and 44 wk for the 10-wk regimen. Semen analysis was performed every 4–6 wk during the first 24 wk of treatment and every 6–12 wk during the rest of the treatment. At the end of the treatment period or at treatment discontinuation, the implant was removed and participants entered the follow up period of at least 24 wk. Semen analysis was performed every 4 wk during follow-up to determine recovery of spermatogenesis.
Blood samples were taken regularly during the study for assessments of testosterone, ENG, LH, and FSH and hematological, biochemical, and lipid parameters. At the day of the TU injection, blood samples were to be taken before the injection. In a subset of men (n = 59 on active treatment), additional blood samples were taken after the first, second, and last TU injection for testosterone assessment. Prostate assessments were done by digital rectal examination and transrectal ultrasonography (if available) at screening, wk 24, end of treatment, and at the end of the 24-wk follow-up period.
Spermatogenesis suppression and recovery
The primary outcome was the percentage of men who had a sperm concentration of 1 million/ml or less at wk 16. Secondary outcomes included the percentage of men who had a sperm concentration below the limit of detection, 0.1 million/ml or less, 1 million/ml or less, or 3 million/ml or less during in-treatment assessments.
After treatment cessation, spermatogenic recovery was expressed as the time needed to achieve a sperm concentration above 20 million/ml.
Semen analyses
Semen samples were to be collected after 2–7 d of sexual abstinence. Full semen analyses at screening and after 24 wk or longer follow-up were performed by the centers, according to the WHO laboratory manual (12). All other semen analyses were performed by one central laboratory (Bio Analytical Research Corporation, Gent, Belgium) using fixated semen samples and a sensitive fluorescence method for low sperm counts (13, 14). The lower limit of detection of this method is 120 sperm per milliliter and the lower limit of quantification 500 sperm per milliliter.
Serum hormone concentrations
Total testosterone serum concentrations were measured by capillary gas chromatography with mass spectrometric detection with a lower limit of quantification of 0.1 ng/ml. The normal range was calculated by using the baseline testosterone concentrations of all included men and ranged from 2.22 to 9.87 ng/ml.
Serum ENG concentrations were measured by RIA with a lower limit of quantification of 30 pg/ml. LH and FSH concentrations were determined by an immunofluorometric assay with a lower limit of quantification of respectively 0.6 and 0.25 U/liter.
Safety outcomes
Information regarding adverse events was obtained by questioning or examining the participant at each visit. All new complaints and symptoms or preexisting complaints and symptoms that increased in severity or frequency during the treatment period were recorded by the investigator. When abnormal blood values were considered clinically relevant in the opinion of the investigator, these were also to be reported as adverse events. All adverse events were classified according to the Medical Dictionary for Regulatory Activities (version 9.0).
Statistical analyses
This study was powered to select the most effective regimen for spermatogenesis suppression. Taking into account a dropout rate of 20%, a sample size of 50 men per group would ensure that if the observed spermatogenesis reduction rate was higher than 90%, the 95% lower confidence bound for true reduction rate is at least 79% (one sided 5% significance level).
NV Organon performed all statistical analysis using SAS (version 9.1.3; SAS Institute, Cary, NC). The per-protocol analysis is presented for efficacy and hormone assessments and the all-subjects-treated analysis for safety. The results of the intent-to-treat analyses for efficacy and hormone assessments were comparable with the per-protocol analysis. The normal range for testosterone concentrations was calculated as the mean ± 1.96 times SD of the log-transformed baseline serum concentrations of all men, followed by backtransformation of this interval to the linear domain.
Comparisons between treatment groups were performed with Fisher exact test or analysis of covariance using baseline values as covariate, if applicable. All reported P values are two sided at a significance level of P = 0.05.
|
Results |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
From December 2003 to September 2004, 589 men were screened for eligibility in the study, 354 were randomized, and 349 treated (Fig. 1
). The last follow-up assessment was in June 2006. The mean age (± SD) of all randomized men was 31 ± 7 yr with a mean body weight of 79 ± 11 kg and a mean body mass index of 24 ± 3 kg/m2. Ninety-eight percent of the men were Caucasian. There were no clinically relevant differences in baseline characteristics, including sperm concentration, between the treatment groups.
|
Spermatogenesis suppression and recovery
Overall, 89% of men on active treatment had a sperm concentration of 1 million/ml or less at wk 16 (Fig. 2). Highest suppression rates were found in the HR implant groups with either TU2 (93%) or TU3 (95%), but the differences between any of the groups were not statistically significant. At wk 20 and 24, the overall percentage of men with a sperm concentration of 1 million/ml or less did not further increase and was 90% at both time points. In the intent-to-treat analyses, the same percentages were found as in the per-protocol analyses, i.e. 89, 90, and 90% of the men had a sperm concentration of 1 million/ml or less at wk 16, 20, and 24, respectively.
|
After suppression to 1 million/ml or less at wk 16, 91% of men (range 82–97%) maintained this suppression up to the end of treatment. Among the 17 men with rebounds, 11 men maintained a sperm concentration of 3 million/ml or less. The highest rebound sperm concentration was 7 million/ml.
Treatment effects were not different between countries or age classes. There was no effect on semen volume.
After treatment cessation, spermatogenesis started to recover rapidly and the median recovery time to a sperm concentration of above 20 million/ml was 15 wk (mean 17 wk, 95% confidence interval 16–18 wk. After 65 wk of follow-up, all men who completed the follow-up phase had recovered. Remarkably, at all assessments during the 24-wk follow-up period, at least two men in the placebo group had sperm concentrations less than 20 million/ml (range 4.5–11.9%) and 28% did not maintain a sperm concentration above 20 million/ml during this period.
Serum hormone concentrations
FSH and LH decreased rapidly after start of treatment (Fig. 3). Mean concentrations were below or just above the detection limit from wk 1 onward. After cessation of treatment, mean LH and FSH levels recovered rapidly. There were no clinically relevant differences between the treatment groups.
|
). Due to a larger decline in ENG concentration with the HR implant, almost comparable concentrations were observed from wk 24 onward.
|
). Mean levels at the end of the injection intervals were at the lower end of the normal range in all dose groups. Testosterone levels were back to baseline 4 wk after end of treatment (first assessment). Safety outcomes
In total, 33 men (9%) discontinued from treatment due to an adverse event, with a higher percentage in the three LR implant groups (range 14–20%) than in the HR implant groups (range 2–6%) and the placebo group (6%) (P < 0.001). The reasons for discontinuation are listed in Table 1. Adverse events were reported by 93% of men on active treatment and 81% of men on placebo treatment. Serious adverse events were reported by nine men, and for all these events, the relationship to the study medication was reported as none or unlikely by the investigator (Table 1). Adverse events such as acne, (night) sweating, mood changes, libido change (28 of 38 men had libido increase), and weight gain were reported more frequently in the active treatment groups, compared with the placebo group (Table 1). Regarding ENG and TU dose, libido change was observed more often in the HR implant groups (18%), compared with the LR implant groups (7%) (P = 0.009), and a trend toward increasing percentages of acne (18, 28, and 32%) and (night) sweating (13, 26, and 40%) was found with increasing TU doses from TU1 to TU3. Gynecomastia was reported in seven active treated men (2%) and three placebo-treated men (6%). At the end of treatment, mean (SD) change from baseline in body weight was 1.0 ± 4.1 kg in the placebo group and 2.5 ± 4.5 kg in the active treatment groups (P = 0.07).
|
Hematology, biochemistry, lipids, and PSA
In the active treatment groups, high-density lipoprotein (HDL)-cholesterol decreased with 13.4 ± 10.6% at wk 12 and 7.4 ± 12.8% at the end of treatment, but also total cholesterol and low-density lipoprotein-cholesterol decreased, compared with baseline (Table 2). Total cholesterol to HDL-cholesterol ratio increased from 3.5 ± 0.9 at baseline to 3.9 ± 1.0 at wk 12, whereas at the end of treatment, the ratio was comparable with baseline (3.6 ± 1.0). There were no clinically relevant differences among the six active treatment groups. SHBG concentrations decreased with 19 ± 17% at wk 42 or 44 compared with baseline.
|
). |
Discussion |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
94% of men). Due to the placebo-controlled, double-blind design of the study, assessment of pregnancy rates was impossible and unethical. Nevertheless, the degree of suppression that was found has been shown to be compatible with contraceptive efficacy in previous studies (3, 4, 15, 18). There were several exclusion criteria defined in this phase II trial. However, it is not expected that these exclusions had a significant effect on the treatment effects, and thus, the results of this trial are considered to be representative for the general population of young males.
In our study, 3% of men failed to suppress to sperm concentrations less than 1 million/ml. This has been seen in most studies and is not completely understood (6, 9, 19). Practical consequence would be the need for a sperm test after a period of 3 or 4 months to discriminate responders from nonresponders, as is needed for vasectomy.
Approximately 9% of men did not maintain suppression after wk 16, but we could not identify a reason for this by looking at hormone levels, FSH, or LH suppression or demographic data. Although it is not known whether these escapes would hamper contraceptive efficacy, for a method to be used widespread, these rebounds should be avoided as much as possible. It is known that ENG causes most of the FSH and LH suppression, but in times with low ENG serum levels, sufficient testosterone is also needed for optimal efficacy (6, 20, 21). At the end of the injection intervals, quite a few men had testosterone levels below the normal range, possibly for a number of weeks. Therefore, maintenance may be improved by increasing the ENG and/or TU dose, the latter possibly by reducing the time interval between TU injections or using other administration routes.
Time to onset of action was fast in our study, with approximately 45% of subjects having a sperm concentration less than 1 million/ml at wk 6 and approximately 90% at wk 12. Median time to recover to values above 20 million/ml was 3.5 months, as also shown by others (8, 9, 22). However, sperm begins to appear in the ejaculate much earlier and return to fertility may have occurred much sooner. Interestingly, only 72% of men on placebo treatment maintained a sperm concentration above 20 million/ml during 24 wk of follow-up. This illustrates the limitations of the recovery cutoff value of 20 million/ml. It is known that there is a large intraindividual variation in sperm concentrations. Because inclusion was based on two sperm concentrations above a specific cutoff value, there is a possibility that certain subjects with normally lower sperm concentrations may have been included in the study. This may account, in part, for the late recovery of sperm concentrations in some individuals. These findings should be taken into account while evaluating recovery from male contraceptive treatment, and therefore, discussions are ongoing to improve the recovery criterion and lower the cutoff value (22, 23).
This is the first study that used central semen analysis, ensuring a more consistent methodology over sites. In our study the rate of azoospermia was lower, compared with other studies (5, 8, 9). Because the percentage of men with a sperm concentration less than 0.1 million/ml and other cutoff points is comparable with earlier studies, the low azoospermia rate likely reflects the low detection limit of our new method. One might argue whether such low detection limit is needed to define male contraceptive efficacy because 1 million/ml is thought to be sufficient (23). However, our results underline the importance of mentioning the detection limit for interpretation and comparison of azoospermia rates.
We do not have an explanation for why more men discontinued due to an adverse event in the LR implant groups, compared with the HR implant groups. However, the overall discontinuation rate was low, which indicates that ENG and TU were well tolerated by most of the men. The placebo-controlled design suggests that the reported incidences of adverse events such as acne, sweating, body weight increase, mood, and libido changes can at least partly be ascribed to the hormonal treatment. Comparable side effects have been reported previously in male hormonal contraceptive studies (8, 9, 24, 25). Nevertheless, percentages may be reduced under more stable physiological testosterone concentrations. For other adverse events such as gynecomastia and prostate-related events, the comparable incidences in the placebo and active treatment groups indicate that these effects are less likely to be treatment related. However, the study was not designed to evaluate long-term safety.
In summary, the combination of an ENG implant with TU injections is a well-tolerated male hormonal method, providing effective and reversible suppression of spermatogenesis. Although the results are good, there is still room for improvement, possibly by adjusting the dose regimen or changing the mode of application.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Disclosure summary: E.M., W.M.K. and M.K. are employed by NV Organon, part of Schering-Plough. J.E. is employed by Bayer-Schering Pharma AG. S.L., A.P., and M.Z. have previously received lecture fees from Organon. F.C.W. has previously consulted for and received lecture fees and grant supports from Organon and Bayer-Schering Pharma. All other authors have nothing to declare.
First Published Online April 15, 2008
Abbreviations: ENG, Etonogestrel; HDL, high-density lipoprotein; HR, high-release; LR, low-release; PSA, prostate-specific antigen; TU, testosterone undecanoate; WHO, World Health Organization.
Received February 4, 2008.
Accepted April 7, 2008.
|
References |
|---|
|
TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  E. Nieschlag Male Hormonal Contraception: Love's Labour's Lost? J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1890 - 1892. [Full Text] [PDF]
|
|
|
|
|
|
Y. Gu, X. Liang, W. Wu, M. Liu, S. Song, L. Cheng, L. Bo, C. Xiong, X. Wang, X. Liu, et al. Multicenter Contraceptive Efficacy Trial of Injectable Testosterone Undecanoate in Chinese Men J. Clin. Endocrinol. Metab., June 1, 2009; 94(6): 1910 - 1915. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
