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Original Studies |
Institute of Reproductive Medicine, University of Münster, D-48129 Münster, Germany
Address all correspondence and requests for reprints to: Prof. Dr. Eberhard Nieschlag, Institute of Reproductive Medicine, University of Münster, Domagkstrasse 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In a phase II clinical trial for hormonal male contraception we evaluated injectable TU in combination with norethisterone enanthate (NETE). NETE has proven useful in female contraception and showed rapid and sustained suppression of serum FSH and testosterone levels in males (19, 20). NETE was also chosen because it produces partial androgenic effects in women, which might be of advantage in male contraception.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The study consisted of 3 arms, each comprising 14 volunteers. All volunteers received im injections of TU. In addition, 1 group received oral levonorgestrel, the second was given oral placebo, and the third group received im NETE injections. While results from the first 2 groups have been published previously (17), we report here the results from the NETE group and again include the placebo group for comparison. The study was approved by the ethics committee of the University and the State Medical Board (Münster, Germany). All volunteers gave written informed consent to participate in the study.
Caucasian men, aged 18–45 yr, were recruited by local press advertisement and were examined for normal general medical history; normal physical condition; normal blood values for routine clinical chemistry, lipids, hematology, and reproductive hormones; and normal semen parameters. Volunteers with clinically relevant abnormalities of the above-mentioned parameters were excluded, and the remaining volunteers were again screened for fulfillment of the inclusion criteria. All 28 volunteers finished the study.
Study design
After the 2 screening visits, all volunteers received im injections of 1000 mg TU dissolved in 4 mL castor oil in study weeks 0, 6, 12, and 18. In addition, at the same intervals 14 volunteers received 200-mg NETE (dissolved in 1 mL castor oil) injections or daily oral placebo treatment over 24 weeks. Examinations consisting of general and genital examination; evaluation of adverse events; measurements of blood biochemistry, lipid profile, hematology, sex hormone-binding globulin (SHBG), prostate-specific antigen (PSA), and reproductive hormones (FSH, LH, PRL, estradiol, testosterone); and semen analysis were performed every 4 weeks. In addition, at every visit all volunteers answered a questionnaire about their condition and sexual behavior. During the recovery period volunteers were seen at study weeks 28, 32, 36, 44, and 52. If semen parameters had not normalized within this period, the recovery period was extended until the volunteer provided a semen sample with normal sperm counts and motility.
In addition to these regular examinations, blood for reproductive hormone analysis was drawn immediately before the following injection in study weeks 6 and 18. In the second pretreatment examination and in study weeks 12, 24, 36, and 52, sonography of scrotal content and transrectal sonography of the prostate were additionally performed. Basal and augmented glucose (oral challenge with 75 g glucose) were determined during the second pretreatment examination and in weeks 12, 24, and week 52.
Blood samples
Venous blood was sampled between 0800–1200 h at every visit after a 10-h fasting period. Blood samples for endocrine determinations were separated at 800 x g and stored at -20 C until evaluation. All other blood parameters were analyzed on the same day.
Assays
Serum levels of LH, FSH, PRL, SHBG, and PSA were determined by highly specific time-resolved fluoroimmunoassays (Autodelfia, Wallac, Inc., Turku, Finland). The lower detection limits for FSH, LH, SHBG, and PSA were 0.25 IU/L, 0.12 IU/L, 6.3 nmol/L, and 0.5 µg/L, respectively. The normal range in our laboratory for LH is 2–10 IU/L, that for FSH is 1–7 U/L, that for PRL is less than 500 mU/L, that for SHBG is 11–71 nmol/L, and that for PSA is less than 4 µg/L. Mean intra- and interassay coefficients of variation during the hormone analysis period were 1.5% and 2.9% for LH, 1.7% and 4.5% for FSH, 0.8% and 4.5% for PRL, 1.0% and 9.6% for SHBG, and 3.2% and 4.3% for PSA, respectively.
Testosterone was determined either with a commercial fluroroimmunoassay (Autodelfia, Wallac, Inc.) or with a commercial enzyme-linked immunosorbent assay (DRG Instruments GmbH, Marburg, Germany). Consecutive samples of every proband were measured with one assay. The lower detection limit for testosterone in the fluoroimmunoassay was 0.28 nmol/L; mean intra- and interassay coefficients of variation were 2.1% and 6.1%, respectively. The lower detection limit in the enzyme-linked immunosorbent assay was 0.24 nmol/L, with mean intra- and interassay coefficients of variation of 3.4% and 9.2%, respectively. Estradiol was measured by highly specific time-resolved fluoroimmunoassays (Autodelfia, Wallac, Inc.), with a lower detection limit of 37 pmol/L and mean intra- and interassay coefficients of variation of 3.7% and 6.4%, respectively. The normal serum level for testosterone is above 12 nmol/L, and the upper normal limit for estradiol is 250 pmol/L.
Clinical chemistry and hematology parameters were analyzed with a Hitachi 947 autoanalyzer (Roche Diagnostics, Mannheim, Germany) and an H3 autoanalyzer (Bayer Corp., Leverkusen, Germany), respectively. A Hitachi 917 autoanalyzer (Roche Diagnostics) was used to quantify serum concentrations of glucose, cholesterol, and triglycerides with enzymatic tests (all from Roche Diagnostics), high density lipoprotein (HDL) cholesterol with a homogenous enzymatic assay (Roche Diagnostics), and apolipoprotein A-I (apoA-I), apoB, and lipoprotein(a) [Lp(a)] with immunoturbidimetric tests (Roche Diagnostics).
Semen analysis
Semen samples were analyzed according to the WHO laboratory manual (21) and were subjected to rigid internal (22) and external quality control (23). In cases of extremely low sperm counts or azoospermia, the ejaculates were centrifuged, and analysis was performed on the sediment. Azoospermia was defined as no sperm found after centrifugation and analysis of the pellet. Severe oligozoospermia was defined as a sperm count of 3 million/mL or less. The volunteers were requested to abstain from sexual activity for 48 h to 7 days before the investigation.
Evaluation of well-being and sexual function
For evaluation of possible psychosexual effects of the treatment, a standardized questionnaire was used. Intensity of sexual thoughts and fantasies, sexual interest and desire, and satisfaction with sexuality during the last week before investigation were rated by the volunteer on an unscaled line ranging from 0–10 cm, with 0 cm reflecting low and 10 cm reflecting high intensity. The intensity was measured using a ruler and was given in centimeters. For evaluation of frequency of erections and ejaculations and morning erections during the last week before investigation, the number of events were estimated by the volunteers. This previously described questionnaire (24) was completed by the volunteers at every visit.
Ultrasonography of testicular volume/transrectal ultrasonography of the prostate
Sonographic (Sonoline Versa Pro, Siemens, Erlangen, Germany) measurements of testes and prostate volumes were performed applying a high frequency 7.5-MHz sector scanner (25). All measurements of prostate volume were performed by transrectal ultrasonography with a mechanical biplanar 7.5-MHz sector scanner (Endo-P, Siemens). Prostate volume was calculated using the ellipsoid method (26).
Statistics
All variables were checked for normal distribution in the
Kolmogorov-Smirnov one-sample test for goodness of fit. Variations
between study groups were evaluated by two-way ANOVA for repeated
measurements. Variations over time within the study group were
evaluated by one-way ANOVA for repeated measurements. In the case of an
overall P < 0.05 in the ANOVA, differences between
baseline values and the following time points were tested by Tukey’s
post-hoc test. If data were not normally distributed,
Friedman ANOVA for repeated measurements followed by Dunn’s multiple
comparison test were used instead. In the case of a single missing
value per time point, the appropriate mean was inserted to allow ANOVA
for repeated measurements. In the case of more than one missing value
per time point, ANOVA was performed. Proportions were
analyzed using the 
2 test. Two-sided
P values of 0.05 were considered significant. All analyses
were performed using the statistical software GraphPad Prism for
Windows, version 2.01 (GraphPad Software, Inc., San Diego,
CA). In general, results are given as the mean ±
SEM.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In general, treatment was well tolerated by all volunteers. Three
volunteers given only TU injections and three volunteers in the NETE
group complained about mild acne during treatment. Three volunteers in
the NETE group experienced increased mild nocturnal sweating. The
significant weight increase from week 20 to week 24 in the NETE group
was reversible, whereas no significant changes could be observed in the
TU alone group or between the groups (Table 1
). No significant changes in physical
symptoms, mood ratings, individual well-being, or frequency of
erections and sexual intercourse were observed at any investigated time
point compared with baseline.
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Ejaculate volumes in both treatment groups remained unchanged
throughout the study period. Treatment with only TU and with TU/NETE
resulted in a significant suppression of sperm counts in all
participants (Fig. 1). In the overall
ANOVA, suppression of sperm counts was significantly more pronounced
(P = 0.004) in the NETE group, although differences
between the groups could not be detected at any single time point.
Compared with baseline, within the groups suppression of sperm counts
was earlier (week 8 vs. week 12) in the NETE group compared
with that in the group given TU alone (Fig. 1). In the TU alone group 7
of 14 and in the NETE group 13 of 14 men reached azoospermia (Fig. 2). The mean time till achievement of
azoospermia was not significantly different between the groups. The
highest azoospermia rate in the TU/NETE group was achieved 8 weeks
after the end of the treatment period (14 weeks after the last
injection). One volunteer with very high initial sperm counts
(mean, 190 million/mL at baseline) could be suppressed only to
oligozoospermia (10.2 million/mL) with a progressive motility of
41% and 13% normal morphology in study week 28. In the TU alone group
5 of 14 achieved severe oligozoospermia (<3 million/mL), and
additionally 2 had lowest sperm concentrations of 4.4 million/mL and
7.2 million/mL, respectively.
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The percentage of normal sperm morphology (Fig. 1) was significantly
reduced between weeks 8 and 36 in the NETE and between weeks 12 and 36
in the TU alone group. No significant differences could be detected
between the groups at any investigated time point.
Hormones
In both groups FSH and LH concentrations were significantly
suppressed from week 4 until week 32 (except for FSH in week 6 in the
TU alone group; Fig. 3). FSH and LH
suppression in the NETE group was significantly more pronounced
compared with that in the group given TU alone (P <
0.0001). A significant difference in FSH levels could be detected
between the groups at week 6. There was a significant increase in PRL
in weeks 4, 8, 16, 18, 20, and 24 in the NETE group and in week 20 in
the TU alone group (Table 1). Between the groups PRL levels were
significantly different in study weeks 8, 16, and 18 (Table 1). The
increase in PRL appeared to be of no clinical relevance.
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). In the NETE
group SHBG (Fig. 3) was significantly decreased from week 4 to week 24,
whereas SHBG remained unchanged (apart from a reduction at week 8) in
the TU alone group. Clinical chemistry and hematology
Values from routine clinical chemistry showed no significant
changes during the study period, except for alkaline phosphatase (Table 2), which was significantly decreased
from week 8 to week 44 in the TU alone group and from week 8 to
week 24 in the NETE group. In the NETE group a significant increase in
erythrocytes (week 12 to week 28), hemoglobin (week 12 to week 32), and
hematocrit (week 4 to week 32) could be detected, whereas hematological
parameters in the TU alone group showed no significant
differences.
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No significant differences from baseline or between the groups
could be observed for apoB and triglyceride at any investigated time
point (Table 2). In the NETE group low density lipoprotein (LDL)
cholesterol (weeks 20, 24, 32, and 36) and cholesterol (week 36) were
significantly increased, and Lp(a) (weeks 8, 16, and 20), HDL
cholesterol (weeks 4, 8, 16, 20, and 24), and apoA-I (weeks 8, 16, and
20) were significantly decreased. In the TU alone group cholesterol
(week 24), HDL cholesterol (week 16 to week 24), and apoA-I (week 4 to
week 24) were significantly decreased compared with baseline values. No
differences were observed for Lp(a) and LDL within the TU alone group
(Table 2). Despite significant overall variations between the groups in
the ANOVA (P < 0.0001) for cholesterol and LDL, no
significant differences were seen at any investigated time point. No
differences between the groups were detected for HDL, Lp(a), and
apoA-I. Basal and augmented glucose levels remained unchanged during
the entire study within and between the groups.
Testes and prostates
In both treatment groups total testes volumes (right plus left
sides) were significantly reduced from week 12 to week 36 and returned
to baseline values at the end of the study (Table 1).
Prostate volumes did not show any significant differences within and
between the study groups during the entire study (Table 1). Except for
a significant elevation of PSA in week 20 in the NETE group, no
differences in PSA could be detected in either group.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In hormonal male contraception long intervals between testosterone injections appear mandatory for general acceptance and a monthly to 3-monthly injection interval appears acceptable to approximately 40% of men (27) and women (28). Although acceptability can only be truly tested in the marketplace, these studies suggest that the 6-weekly injection interval in our study is in the range of acceptability for quite a number of men. In addition, TU provides mostly normal serum testosterone levels; elevated levels were only seen 2 weeks after the last TU injections. At this time point pharmacokinetic studies also showed maximum concentrations (tmax) (13, 14). In another study with TU alone azoospermia was achieved in 11 of 12 and 12 of 12 Chinese volunteers receiving 500 or 1000 mg TU at 4-week intervals (15). In our study with Caucasian men azoospermia could be achieved only in 7 of 14 volunteers, whereas another 5 of 14 volunteers became severely oligozoospermic. Compared with weekly injections of TE, im injections of TU provide similar suppression of gonadotropins and spermatogenesis in Chinese and Caucasian volunteers, with the great advantage of longer injection intervals.
Studies in Caucasians using a combination of TE and depot medroxyprogesterone have shown azoospermia rates of 60% (29). More recent trials have focused on the combination of TE and desogestrel (30) or levonorgestrel (LNG) (4, 5). Desogestrel has shown promising initial results, with azoospermia obtained in all 8 volunteers given oral 300 µg desogestrel daily and 50 mg TE weekly. However, in the other groups with a higher androgen dose (100 mg/week) or a lower desogestrel dose (daily 150 µg desogestrel, orally) the effect was much less pronounced (66% azoospermia). Furthermore, results of studies with a combination of a desogestrel and a long-acting testosterone ester are not available. Among the studies using TE (100 mg/week) in combination with LNG, the best results were obtained with a daily LNG dose of 250 µg, which resulted in azoospermia in 14 of 18 and severe oligozoospermia in 2 additional volunteers (5). However, when combined in different regimens with long-acting im injections of 250 mg TU every 4 weeks (31) or 1000 mg TU every 6 weeks (32), the combination with LNG implants (31) or 250 µg orally (17) achieved azoospermia only in 6 of 16 Chinese and 7 of 14 Caucasian volunteers, respectively. Better suppression of spermatogenesis was achieved when TE (100 mg/week) was combined with cyproterone acetate (CPA; 25–100 mg), resulting in azoospermia in all volunteers (7, 8). However, 16 weeks after initiation of the treatment a significant reduction of hemoglobin was seen under these CPA doses, whereas a lower CPA dose (12.5 mg/day) showed low efficacy (8). This is in agreement with older studies using 5–10 mg CPA (32). Whether CPA at higher doses in combination with TU injections will lead to similar results as those obtained with TE, but without hemoglobin decrease, remains to be investigated.
In view of the results achieved for hormonal male contraception with LNG and CPA, a search for more appropriate gestagens is warranted. Among the candidates, we chose NETE because of its long-lasting gonadotropin suppressive effect and high efficacy in women (33). In addition, as NET binds to the androgen receptor, resulting in androgenic activity equal to approximately 10% that of testosterone (34), it exhibits androgenic properties undesirable in women but that might be of advantage in male contraception. In a pharmacokinetic study we could confirm that the NETE profile in men is similar to that in women with comparable maximal concentrations, area under the curve, time points of maximal concentrations, and terminal elimination half-life (19, 35). In preclinical studies in bonnet monkeys monthly im injections of NETE resulted in azoospermia in all monkeys within 60–150 days (36). In humans NET acetate (10 mg/day, orally) was capable of suppressing spermatogenesis to azoospermia in all 5 volunteers within 2 months when combined with 250 mg percutaneous testosterone gel daily (37). The present study confirms the good results of these initial studies, with 13 of 14 volunteers achieving azoospermia. Why 1 volunteer in the NETE group did not achieve azoospermia remains unclear. However, he also showed a marked suppression of spermatogenesis, as his sperm concentration declined from 189.5 million/mL at baseline to 10.2 million/mL in week 28. Gonadotropin suppression in this volunteer was not as pronounced as that in volunteers becoming azoospermic. One might speculate that adjustments of the doses or frequency of injections could also cause azoospermia in this man. However, in general, suppression of gonadotropins was significantly better than that in the TU alone group during the entire treatment period. As the suppression of gonadotropins was similar with LNG (17) or NETE, we attribute the better suppression of spermatogenesis to an additional direct testicular effect of NET. It was shown in rats that unilateral NET implants in the epididymal fat pad lead to drastic reduction of testicular size and weight as well as sperm production at the ipsilateral site, whereas the contralateral testis was not affected (38).
The rapidity and the degree of gonadotropin suppression observed with TU/NETE are comparable to or better than those seen with other regimens using GnRH antagonists (39, 40, 41, 42, 43), CPA (7, 8), or desogestrel in combination with TE (50 mg/week) (30). Altogether 45 volunteers were treated with daily GnRH antagonist injections in male contraception trials. In these studies azoospermia and severe oligozoospermia were obtained in 82% and 13% of volunteers, respectively (39, 40, 41, 42, 43). Thus, results using GnRH antagonists or NETE are comparable. However, the necessity of daily sc injections of the GnRH antagonist make this approach impractical, whereas NETE has to be injected only every 6 weeks.
In general, treatment with TU and NETE was well tolerated by all volunteers, and none of our volunteers discontinued treatment. However, as in other studies with im testosterone injections, local pain and induration at the injection site as well as mild acne and weight gain can occur occasionally. In addition, increased nocturnal sweating seems to be associated with the gestagen treatment. Other unfavorable effects were TU-associated significant decreases in the antiatherogenic parameters HDL cholesterol and apoA-I and an increased atherogenic LDL cholesterol/HDL cholesterol index. These results are consistent with the results of other studies, which have shown that exogenous testosterone application influences atherogenic risk factors (for review, see Ref. 44). In the NETE group this effect is more pronounced, as gestagens are known to decrease HDL cholesterol (45, 46). In addition, a significant increase in LDL cholesterol, erythrocytes, hematocrit, and hemoglobin was seen in the TU plus NETE group. However, these anabolic effects of TU were only moderate, and values did not exceed normal values, casting doubt on the clinical relevance of these findings in long-term studies. However, extending the injection interval after the third or fourth injection might overcome the possible risk of polycythemia in long-term users. The decrease in total alkaline phosphatase might reflect decreased bone formation. However, as no markers for bone resorption have been measured, and androgens are known to increase bone formation in hypogonadal patients (47), the clinical relevance of this finding remains to be elucidated.
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Acknowledgments |
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Footnotes |
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Received February 15, 2000.
Revised June 23, 2000.
Revised August 25, 2000.
Accepted September 12, 2000.
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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| 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 |
). Results are the mean ± SEM of all
volunteers; if volunteers achieved azoospermia, values for motility and
morphology are counted as zero. Significant differences from baseline
are indicated as stars. Significant differences between
the groups are indicated as lowercase letters. Injection
time points are indicated as arrows.
