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Endocrine Care |
Institute of Reproductive Medicine of the University (A.K., T.H., K.K., S.V.E., E.N.), D-48129 Münster, Germany; and Schering AG (I.S., A.R.), D-13342 Berlin, Germany
Address all correspondence and requests for reprints to: Dr. Eberhard Nieschlag, Institute of Reproductive Medicine of the University, Domagkstr. 11, D-48129 Münster, Germany. E-mail: nieschl{at}uni-muenster.de
Abstract
Suppression of spermatogenesis to azoospermia is the goal of hormonal male contraception based on T combined with gestagens. The combination of the long-acting T, ester testosterone undecanoate (TU), with norethisterone (NET) enanthate (E) showed high efficacy. In the present study, we tested the validity of this approach by varying the NET dose and mode of application. The aim of the study was to achieve high rates of suppression of spermatogenesis as reflected by sperm counts, monitor gonadotropins as well as other hormones, and evaluate any possible side effects. In a phase II clinical trial, groups of normal volunteers received: 1000 mg TU im at wk 2, 6, 12, and 18 combined with 200 mg NETE im at wk 0, 6, 12, and 18 (group I); 1000 mg TU im and 400 mg NETE im at wk 0, 6, 12, and 18 (group II); and 1000 mg TU im at wk 0, 6, 12, and 18 with daily oral NET acetate (NETA) from wk 0 to 24 (group III). In all groups marked suppression of gonadotropins resulted in a significant decrease of spermatogenesis and azoospermia in 13/14, 11/12, and 12/14 men in groups I to III, respectively. The remaining men all had less than 1 million sperm/ml. Reversible side effects included increase in body weight, erythrocytes, hemoglobin, and hematocrit and decrease in high-density lipoprotein cholesterol and alkaline phosphatase in all groups and increase in liver enzymes in the oral NETA group. This study documents the high efficacy of TU in combination with NET and confirms that this dose and mode of application (1000 mg TU im every 6 wk plus 400 mg NETE im every 6 wk or plus 10 mg daily oral NETA) is as effective as the previously reported regimen containing 1000 mg TU + 200 mg NETE im every 6 wk. The contraceptive efficacy of this combination of TU and NETE should be evaluated in further clinical trials.
APPROACHES TO HORMONAL male contraception are based on the suppression of gonadotropins, leading to suppression of spermatogenesis. In initial studies of male hormonal contraceptives, it could be shown that pregnancy rates are inversely correlated to residual sperm concentrations and azoospermia resulted in a Pearl index of 0.0 ( 1, 2). These studies were based on weekly injections of testosterone enanthate (TE) and azoospermia was achieved in only two-thirds of Caucasian and almost all Chinese volunteers. To improve efficacy, T was combined with different agents ( 3). Among the most promising agents were GnRH antagonists ( 4), cyproterone acetate ( 5), desogestrel ( 6), and norethisterone enanthate (NETE) ( 7). Most of these regimens required weekly or biweekly im injections of TE, which are not appropriate for long-term use. However, a recent trial has shown sufficient suppression of spermatogenesis with Desogestrel (DSG) in combination with T implants ( 8). Of the injectable T esters, only testosterone undecanoate (TU) ( 7, 9, 10, 11, 12) and testosterone buciclate ( 13) have half-lives long enough to warrant long injection intervals and hence long-term acceptance. In an initial study, we therefore evaluated the potential of 1000 mg TU in combination with 200 mg NETE injected at 6-wk intervals or with oral (250 µg daily) levonorgestrel ( 7, 9). Suppression of spermatogenesis to azoospermia in 13 of 14 volunteers was achieved with the combination of TU and norethisterone, making this a first choice for further studies of hormonal male contraception ( 7).
In continuation of our previous trial, we evaluated the potential of TU plus norethisterone in a further three-arm phase II clinical trial. As in other studies, delayed T substitution showed better efficacy, compared with combined administration ( 14). In the first arm, TU was given 2 wk after initial NETE administration. In the second arm, the NETE dose was double that of our previous study ( 7) to enhance gonadotropin suppression. In the third arm, we investigated the efficacy of oral NET acetate, which has shown promising results when combined with T gel application ( 15).
Subjects and Methods
Subjects
Sixty Caucasian men, aged 18–45 yr, who responded to press advertisements, were evaluated by obtaining medical history, physical examination, and tests for blood chemistry, plasma lipids, hemoglobin, hematocrit, blood cell counts, reproductive hormones, and semen analysis. Volunteers were excluded because of asthenozoospermia (n = 7), oligoasthenozoospermia (n = 4), oligozoospermia (n = 2), sonographically suspect hyperechogenic foci of the tests (n = 1), liver enzyme increases (n = 2), hematologic disturbances (n = 1), and on demand of the volunteer (n = 1). The remaining volunteers were again screened for fulfillment of the inclusion criteria. A priori analysis revealed that 10 volunteers (per arm) are sufficient to yield information about the suppression of spermatogenesis and about side effects with a power of 0.8. However, in consideration of an estimated dropout rate of about 30%, 14 volunteers were enrolled in each group. However, the sample size was not determined to detect differences in azoospermia or oligozoospermia rates between the groups. The allocation of a randomization number was made in chronologically ascending order based on the sequence of arrival of the patients at the study center. A third-party randomization using randomization blocks was used. Fourteen volunteers were included per treatment arm. Of 42 volunteers initially included, 40 volunteers finished the study and were evaluated for efficacy.
Study design
The study was approved by the Ethics Committee of the University and the State Medical Board, Münster. All volunteers gave written informed consent to participate in the study. After the two screening visits, volunteers were randomized to the following groups for a treatment period of 24 wk. Dosages of TU and NETE were based on our previous studies ( 7, 9) and were modified to give rise to:
Group I: Injections of 200 mg NETE at study wk 0, 6, 12, and 18 plus injections of 1000 mg TU at study wk 2, 6, 12, and 18 (T free window).
Group II: Injections of 1000 mg TU together with 400 mg NETE at study wk 0, 6, 12, and 18.
Group III: Injections of 1000 mg TU at study wk 0, 6, 12, and 18 combined with daily oral 10 mg norethisterone acetate (NETA) from week 0 to 24.
TU (1000 mg) and NETE (200 mg) were dissolved in 4 ml and 1 ml castor oil, respectively. General and genital examination, evaluation of adverse events, SHBG, prostate-specific antigen (PSA), reproductive hormones (FSH, LH, PRL, E2, T, SHBG), and semen analysis were performed every 4 wk during the treatment period. In addition, at every visit all volunteers answered a questionnaire about their well-being and sexual behavior. During the 28-wk recovery period, volunteers were seen at study wk 28, 36, 44, and 52. If semen parameters had not normalized by wk 52, 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 wk 6 and 18. At the second pretreatment examination and in study wk 12, 24, 36, and 52, sonography of scrotal content and transrectal sonography of the prostate as well as measurements of blood biochemistry, lipid profile, and hematology were additionally performed.
Measurements
Blood samples. Venous blood was sampled between 0800 and 1200 h at every visit after a 10-h fasting period. Blood samples for endocrine determinations were separated at 800 g and stored at -20 C until evaluation. All other blood parameters were analyzed on the same day.
Assays
Consecutive samples of every single proband were measured within one assay. Serum levels of LH, FSH, PRL, SHBG, and PSA were determined by highly specific time-resolved fluoroimmunoassays (Autodelfia, Perkin-Elmer, Wallac Inc., Turku, Finland). The lower detection limits were 0.25 IU/liter FSH, 0.12 IU/liter LH, 6.3 nmol/liter SHBG, and 0.5 µg/liter PSA, respectively. The normal range in our laboratory for LH is 2–10 IU/liter, 1–7 U/liter for FSH, less than 500 mU/liter for PRL, 11–71 nmol/liter for SHBG, and less than 4 µg/liter for PSA. Mean intra- and interassay coefficients of variation during hormone analysis were 1.4% and 4.9% for LH, 1.4% and 4.7% for FSH, 1.0% and 3.0% for PRL, 1.4% and 8.3% for SHBG, and 1.4% and 4.9% for PSA, respectively.
T was determined with a commercial ELISA (DRG Instruments GmbH, Marburg, Germany). The lower detection limit for T was 0.24 nmol/liter with mean intra- and interassay coefficients of variation of 3.9% and 9.6%, respectively. E2 was measured by highly specific time-resolved fluoroimmunoassays (Autodelfia, Perkin-Elmer Corp. Wallac, Inc.) with a lower detection limit of 37 pmol/liter and mean intra- and interassay coefficients of variation of 4.8% and 8.4%, respectively. The normal serum level for T is above 12 nmol/liter and the upper normal limit for E2 is 250 pmol/liter. The formula suggested by Vermeulen et al. ( 16) was used for calculations of free T. Clinical chemistry and hematology parameters were analyzed by routine autoanalyzers as published previously ( 9).
Semen analysis
Semen samples were analyzed according to the World Health Organization Laboratory Manual ( 17) and subjected to rigid internal ( 18) and external quality control ( 19). 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 lowest detectable value of sperm concentration in our laboratory using a Neubauer chamber is 0.1 million sperm per milliliter. If initially only one sperm in two chambers could be counted or sperm were seen only after centrifugation of the ejaculate, the ejaculate was centrifuged and sperm concentration was classified as less than 0.1 million per milliliter. The volunteers were requested to abstain from sexual activity for 48 h to 7 d before 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 week before investigation were rated by the volunteer on an unscaled line ranging from 0 to 10 cm with 0 cm reflecting lowest and 10 reflecting highest intensity. For evaluation of frequency of erections, ejaculations, and morning erections during the week before investigation, the number of events was estimated by the volunteers. This previously described questionnaire ( 20) was completed by the volunteers at every visit.
Ultrasonography of testicular volume/transrectal ultrasonography of the prostate
Sonographic (Ultrasound scanner type 2002 ADI, B\|[amp ]\|K Medical, Gentofte, Denmark) measurements of testes and prostate volumes were performed applying a high-frequency 7.5-MHz convex scanner ( 21). All measurements of prostate volume were performed by transrectal ultrasonography with a mechanical biplanar 7.5-MHz sector scanner (B\|[amp ]\|K Medical, type 8558/T). Prostate volume was calculated using the ellipsoid method ( 21).
Statistics
All variables were checked for normal distribution in the Kolmogorov-Smirnov one-sample test for goodness of fit. Variations among 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 case of an overall P less than 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 was used instead. In case of a single missing value per time point, the appropriate mean was inserted to allow ANOVA for repeated measurements. In case of more than one missing value per time point, ANOVA was performed. Proportions were analyzed using the chi-square test. Two-sided P values of 0.05 were considered significant. All analyses were performed using the statistical software GraphPadPrism for Windows version 2.01 (GraphPad Software, Inc., San Diego, CA). In general, results are given as mean ± SEM.
Results
General well-being and sexual function
In general, treatment was well tolerated by all volunteers. However, two volunteers in group II dropped out during the treatment phase at study wk 12 and 20 because of increased nocturnal sweating and weight gain (7.1 kg), respectively. Two volunteers in group I, three volunteers in group II, and none in group III complained about mild acne during treatment. One volunteer in group I, one volunteer in group II, and three volunteers in group III complained about mammillary pain/induration during treatment. Three volunteers in group I, five volunteers in group II, and five volunteers in group III complained about increased nocturnal sweating during treatment. One volunteer in each group complained about increased general sweating during treatment. Further adverse events possibly related to the medication were: subjectively increased aggressive behavior (one volunteer, group I), pain at the injection site (one volunteer, group II), and short duration of erectile dysfunction (one volunteer, group III). Except for three volunteers complaining about mammillary pain/induration, all other adverse events mentioned above, which were possibly related to the study medication, had disappeared at the end of the treatment period.
In all treatment groups, a significant increase of body weight (Table 1
). and body mass index was noticed. In treatment groups I and III, a significant increase was detected in the number of weekly ejaculations, which was significant, compared with baseline for treatment group III at study wk 8 (see Fig. 5). Except for the above-mentioned changes, 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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Treatment in all groups resulted in a significant suppression of sperm counts in all participants (Fig. 1). No differences could be detected among the groups. Compared with baseline, within-group suppression of sperm counts was significant for wk 8 to 36 for all groups (Fig. 1). In group I, 13 of 14, in group II, 11 of 12, and in group III, 12 of 14 men reached azoospermia (Fig. 2). The remaining four men showed severe oligozoospermia with sperm counts of less than 0.1 million/ml (group I), 0.7 million/ml (group II), less than 0.1 million/ml, and 0.1 million/ml (group III). Mean time till achievement of azoospermia was not significantly different among groups and was 16.3 plus or minus 2.0, 16.7 plus or minus 2.1 and 16.0 plus or minus1.9 weeks for group I, II, and III, respectively. Highest azoospermia rates were achieved at study wk 24 in all study groups. Both volunteers who dropped out at study wk 12 and 20 were azoospermic at the time point of dropout.
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Forward sperm motility (grades a + b) was significantly reduced, compared with baseline in group I (wk 8 to 36), group II (wk 16 to 36), and group III (wk 12 to 28). Among the groups no difference could be detected (Fig. 1
).
Percentage of normal sperm morphology (Fig. 1) was significantly reduced, compared with baseline in group I (wk 12 to 36), group II (wk 8 to 36), and group III (wk 8 to 28). No significant differences could be detected among the groups at any investigated time point.
Hormones
In group I, FSH and LH concentrations were significantly suppressed from wk 4 until wk 36 and in both other groups from wk 4 until wk 28 (Fig. 3). No differences among the groups could be detected for LH. However, FSH values and percent suppression of FSH in group I were significantly lower, compared with group III in the ANOVA for repeated measurements. All volunteers in all groups had undetectable FSH levels at some time points. However, nine volunteers in group I, seven volunteers in group II, and nine volunteers in group III had persistent undetectable FSH levels during the treatment phase. There was a significant increase in PRL from wk 4 until wk 24 (with the exception of wk 6 for group II) for all treatment groups (Table 1). Among the groups PRL levels were significantly lower in group II, compared with both other groups. The increase in PRL appeared to be of no clinical relevance.
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). Some significant elevations of T levels were evident 2 wk after the second and fourth injection (Fig. 4). Among the groups no significant differences in T serum levels could be detected. All groups showed significant elevations of free T 2 wk after injection (Fig. 4). Among the groups, free T levels were significantly lower in group III, compared with both other groups, which were otherwise not significantly different. Compared with baseline, E2 levels showed some significant elevations 2 wk after the second and fourth injection and significant decreases before the second injection (Fig. 4). Among the groups, E2 levels were significantly higher in group I, compared with both other groups. Compared with baseline, SHBG was significantly decreased in all groups from wk 2 to wk 28, from wk 4 to wk 36 and from wk 4 to wk 28 for group I, II, and III, respectively (Fig. 4). SHBG levels in group III remained higher (P < 0.0001), compared with both other groups, which were not significantly different.
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During the treatment period (in group I in addition at wk 36), alkaline phosphatase was decreased in all treatment groups (Fig. 5), compared with baseline. No differences among the groups were evident. Although they remained unchanged in the other groups (Table 2), significant elevations of lactate dehydrogenase and glutamate pyruvate transaminase were observed for groups III and I for study wk 24 and 36, respectively. These increases appeared to be of no clinical relevance. Compared with baseline, a significant increase in erythrocytes (Fig. 5), hemoglobin (Table 2), and hematocrit (Fig. 5) was observed in group II. Significant variations over time could be also found for group I. However, compared with baseline, only a significant increase in hematocrit could be detected for wk 24. In group III no significant variations over time could be found for erythrocytes, hemoglobin, and hematocrit. Significant variations over time could further be found for platelets (Table 2) in all groups. Compared with baseline, significant increases of platelets could be found for group III in wk 12 and 24, but platelets in group I were significantly decreased in wk 36, compared with baseline. All other values from routine clinical chemistry and hematology showed no significant variations over time.
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No significant differences to baseline or among the groups could be observed for Lp (a), low-density lipoprotein cholesterol (Table 2), and triglycerides at any investigated time point for any group. Total cholesterol (Table 2) showed significant variations over time for groups I (P = 0.02) and III (P = 0.001), which were significantly elevated, compared with baseline for wk 36 in group III. In all groups significant variations over time (P < 0.01) for high-density lipoprotein cholesterol (HDL-C) could be detected with significant decreases, compared with baseline, for wk 12 and wk 12 and 24 for group I and III, respectively (Table 2). Significant variations (P < 0.01) of the total cholesterol/HDL-C ratio were observed for groups II and III, which were significantly elevated, compared with baseline, for wk 12 and 24 (Table 2). The ratio of total cholesterol to plasma HDL-C was significantly lower in group II, compared with groups I and III (P < 0.01).
Testes and prostates
In all treatment groups, total testes volumes (right plus left side) were significantly (P < 0.0001) reduced from wk 12 to wk 36 and returned to baseline values at the end of the study (Table 1). Prostate volumes did not show any significant differences, compared with baseline (Table 1). In all groups no significant differences in PSA could be detected.
Discussion
Most potential users of a male contraceptive would prefer an injection-independent application modality ( 22). However, except for the combination of NETA with transdermal T gel, injection, or implantation-free approaches have failed to suppress spermatogenesis sufficiently so far ( 23, 24, 25). However, surveys indicated that a monthly to three-monthly injection interval would be acceptable to approximately 40% of users ( 22), suggesting that the 6-wk injection interval in our study is in the range of acceptability. With the T dose given, highest measured mean serum T levels were always under 26 nmol/liter (i.e. in the normal range in all groups). At the end of the treatment period, mild androgen-related symptoms like acne or mammillary pain or induration and slight and inconsistent elevations of red blood cell count parameters could be observed in some volunteers. In agreement with our previous studies and in view of the stepwise increase in T levels at the time point of injection (Fig. 4), our findings suggest that an extension of the injection intervals to 8 or 10 wk after wk 18 might be possible without losing efficacy. This should avoid androgen levels in the upper normal range at the end of the study and increase the long-term acceptability of the regimen.
Based on the concept that the stimulatory action of T on spermatogenesis may be less pronounced in the regressed than in the normal testis, studies in monkeys have shown that delayed T substitution showed better efficacy than combined administration (14). Corresponding clinical studies with GnRH antagonists and using a T-free interval (26, 27) have shown a tendency toward better efficacy (88% vs. 76% azoospermia) than trials with simultaneous administration (28, 29). We could not confirm a beneficial effect of the T-free initial phase, compared with our previous study (7) or to study groups I and II, because all groups showed comparable suppression of spermatogenesis and similar rates of azoospermia.
With regard to spermatogenic suppression, 400 mg NETE or oral NETA were not more effective than the 200 mg given im in this or our previous study (7). This is in agreement with a previous study in humans that showed no benefit of daily oral treatment with 5 or 10 mg NETA when combined with 250 mg percutaneous T gel daily (15). In addition in our study, both groups showed more potential gestagenic side effects such as increased nocturnal or general sweating, compared with the 200-mg group. Significantly higher FSH values in the NETA group, compared with the 200 mg NETE group, suggested lower gonadotropin suppression by the NETA medication, casting doubts on the efficacy of a 5-mg NETA dose when combined with 6 weekly injections of TU.
Compared with other trials of hormonal male contraception, only a very limited number of trials combining a T preparation with GnRH antagonists (4, 26, 27, 28, 29), cyproteronacetate (CPA) (5, 30), or DSG (6, 8) have shown efficacy comparable to NET. However, the number of volunteers involved in the studies is small and allows only preliminary conclusions. Of the 47 volunteers treated with daily GnRH antagonist injections, azoospermia and sperm concentrations below 1 million per milliliter were obtained in 83% and 85% of volunteers, respectively. As with NETE, with 12.5–100 mg CPA daily, suppression of spermatogenesis was better than with the GnRH antagonists because 90% of the 20 volunteers reached azoospermia and all achieved sperm concentrations below 1 million/ml. However, so far, administration of GnRH antagonists or CPA offered no realistic alternative to the current regimen. In addition to the lower efficacy of GnRH antagonists, compared with NETE, the necessity of daily sc injections of the GnRH antagonist combined with high costs make this approach impractical. The combination of TE with CPA at higher doses, however, led to an unacceptable reduction of hemoglobin 16 wk after initiation of the treatment, but lower CPA doses showed lower efficacy in older studies using 5–10 mg CPA (31).
Because of the problems with the GnRH antagonists and CPA regimens, so far, the 19-nortestosterone-derived synthetic progestogens DSG and NET seem to offer the best option for a potent male contraceptive with acceptable side effects. Recent trials have investigated the combination of TE (6, 32) or T implants (8) and 150 or 300 µg DSG. As with NETE (7), only one volunteer failed to suppress sperm concentration sufficiently with nadir sperm concentrations remaining at 16.3 million/ml at wk 24 (6). Compared with DSG, we achieved better rates of azoospermia (91% vs. 77%) and suppression of spermatogenesis below 1 million/ml (98% vs. 93%) with the norethisterone preparations and the long-acting testosterone ester, TU. This slight tendency toward better efficacy with a T/norethisterone combination might be owing to a suspected but unknown direct testicular effect of norethisterone or its metabolites. In addition, two of the three volunteers who did not suppress below 1 million sperms/ml in the DSG groups received 150 µg DSG in combination with 50 mg TE, which might be a suboptimal T dose (32). Whether DSG at higher doses in combination with a long-acting injectable testosterone ester provides similar results remains to be investigated.
Although the treatment was generally well tolerated, two volunteers in group II discontinued. However, two volunteers of group II discontinued treatment because of probably androgen-related weight gain (wk 20) and probably gestagen-related increased nocturnal sweating. Moreover, other volunteers also experienced mild, probably androgen-related adverse events, which were tolerable for the rest of the volunteers. In addition, all groups showed a reversible increase in erythrocytes, hemoglobin, hematocrit, and body weight, possibly androgen related. Although these changes were not significant for all groups and did not exceed the normal range, these symptoms could be avoided by longer injection intervals after wk 18. In addition, a decrease in alkaline phosphatase was evident in all groups. The physiological basis for this decrease is not known. The decrease in total alkaline phosphatase might reflect decreased bone formation. However, because no markers for bone resorption have been measured and androgens are known to increase bone formation in hypogonadal patients (33), the clinical relevance of this finding remains to be elucidated. Compared with group I and our previous study (7), the gestagenic side effects were more apparent in the higher-dose groups II and III. Because the higher doses lead to no better results with respect to efficacy, the higher rate of gestagenic side effects favors the use of lower norethisterone doses. Comparing the injectable and oral NET medications in NETE groups, no changes in liver enzymes could be observed. In the NETA group, significant elevations of lactate dehydrogenase and glutamate pyruvate transaminase were seen. Direct effects of NETA on the liver might also explain the only slightly reduced SHBG levels in the NETA group, compared with the NETE groups. Therefore, NETA appears to be the poorer choice, compared with NETE. The decreases of the antiatherogenic HDL-C and increases in the atherogenic cholesterol/HDL-C index in all groups appear to be a combination of gestagen- and androgen-related effects. These results are consistent with other studies that have shown that exogenous T and gestagen application influences atherogenic risk factors (6, 7, 34). The increases in atherogenic risk factors were more pronounced in the NETA group, compared with the NETE groups.
The reasons for the PRL increase remain unknown. In our previous studies with TU for contraception, PRL levels in the androgen plus gestagen-treated groups were also significantly higher, compared with placebo (7, 9). In the current study, however, PRL levels in the 400-mg dose group were significantly lower than in the 200-mg dose group. A direct role for progesterone in the synthesis and release of PRL within the hypothalamus is not as well described as that of E2. Some studies in women report enhancement of PRL secretion, whereas the majority reports no effect or inhibition of PRL secretion in response to progesterone including norethisterone (35). In addition, E2 levels are known to increase PRL secretion in women and are (although modestly and mostly not significant) during most time points higher than pretreatment E2 levels in all groups (Fig. 4). Therefore, we attribute the modest increase in PRL to a combined effect of TU and norethisterone. However, in view of the stable and completely reversible elevation of serum PRL levels, so far, we see no clinical relevance of this elevation.
In conclusion, the present study confirms the results of our initial study with the combination of norethisterone and TU (7), producing a profound suppression of gonadotropins and spermatogenesis. However, the higher NETE dose, the T-free window at the beginning, or the oral NETA medication does not offer additional benefits. In contrast, the 400-mg NETE group as well as the NETA group show a higher rate of nocturnal and general sweating as probably gestagenic side effects. In the NETA group, an increase in artherogenic risk factors and liver burden was evident. Nevertheless, the efficacy in all groups of the combination of TU and norethisterone has proven better than in nearly all other previous studies for hormonal male contraception. In view of these results, the combination of TU and the lower dose of NETE has considerable potential for the development of a hormonal male contraceptive.
Acknowledgments
We are grateful to Anke Richter, Dirk-Andreas Schütt, Susanne Wegener, and Gisela Wachsmuth-Melm of Schering AG (Berlin, Germany) for monitoring the study according to GCP guidelines. We thank Anita Broschk, Anne Erpenbeck-Leuer, Heidi Kersebom, Diane Koester, Raphele Kürten, Külli Nurmik, Sabine Rehrs, Daniela Schmidt, Nicole Terwort, and Katrin Wardecki for technical assistance and Susan Nieschlag, M.A., for language editing of the manuscript.
Footnotes
This work was supported in part by the Bundesministerium für Gesundheit, Schering AG, and the Deutsche Forschungsgemeinschaft Confocal Research Group, the Male Gamete: Production, Maturation, Function (Ni 130/15).
Abbreviations: CPA, Cyproteronacetate; DSG, Desogestrel; HDL-C, high-density lipoprotein cholesterol; NETA, norethisterone acetate; NETE, norethisterone enanthate; PSA, prostate-specific antigen; TE, testosterone enanthate; TU, testosterone undecanoate.
Received June 12, 2001.
Accepted October 29, 2001.
References
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K. L. Matthiesson, P. G. Stanton, L. O'Donnell, S. J. Meachem, J. K. Amory, R. Berger, W. J. Bremner, and R. I. McLachlan Effects of Testosterone and Levonorgestrel Combined with a 5{alpha}-Reductase Inhibitor or Gonadotropin-Releasing Hormone Antagonist on Spermatogenesis and Intratesticular Steroid Levels in Normal Men J. Clin. Endocrinol. Metab., October 1, 2005; 90(10): 5647 - 5655. [Abstract] [Full Text] [PDF]
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B. D. Anawalt, J. K. Amory, K. L. Herbst, A. D. Coviello, S. T. Page, W. J. Bremner, and A. M. Matsumoto Intramuscular Testosterone Enanthate Plus Very Low Dosage Oral Levonorgestrel Suppresses Spermatogenesis Without Causing Weight Gain in Normal Young Men: A Randomized Clinical Trial J Androl, May 1, 2005; 26(3): 405 - 413. [Abstract] [Full Text] [PDF]
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M. C. Meriggiola, A. Costantino, F. Saad, L. D'Emidio, A. M. Morselli Labate, A. Bertaccini, W. J. Bremner, I. Rudolph, M. Ernst, B. Kirsch, et al. Norethisterone Enanthate Plus Testosterone Undecanoate for Male Contraception: Effects of Various Injection Intervals on Spermatogenesis, Reproductive Hormones, Testis, and Prostate J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2005 - 2014. [Abstract] [Full Text] [PDF]
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C. J. Hay, B. M. Brady, M. Zitzmann, K. Osmanagaoglu, P. Pollanen, D. Apter, F. C. W. Wu, R. A. Anderson, E. Nieschlag, P. Devroey, et al. A Multicenter Phase IIb Study of a Novel Combination of Intramuscular Androgen (Testosterone Decanoate) and Oral Progestogen (Etonogestrel) for Male Hormonal Contraception J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 2042 - 2049. [Abstract] [Full Text] [PDF]
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M. Schubert, T. Minnemann, D. Hubler, D. Rouskova, A. Christoph, M. Oettel, M. Ernst, U. Mellinger, W. Krone, and F. Jockenhovel Intramuscular Testosterone Undecanoate: Pharmacokinetic Aspects of a Novel Testosterone Formulation during Long-Term Treatment of Men with Hypogonadism J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5429 - 5434. [Abstract] [Full Text] [PDF]
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B.M. Brady, M. Walton, N. Hollow, A.T. Kicman, D.T. Baird, and R.A. Anderson Depot testosterone with etonogestrel implants result in induction of azoospermia in all men for long-term contraception Hum. Reprod., November 1, 2004; 19(11): 2658 - 2667. [Abstract] [Full Text] [PDF]
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 G. Shetty, C. C. Y. Weng, O. U. Bolden-Tiller, I. Huhtaniemi, D. J. Handelsman, and M. L. Meistrich Effects of Medroxyprogesterone and Estradiol on the Recovery of Spermatogenesis in Irradiated Rats Endocrinology, October 1, 2004; 145(10): 4461 - 4469. [Abstract] [Full Text] [PDF]
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D. B. O'Connor, J. Archer, and F. C. W. Wu Effects of Testosterone on Mood, Aggression, and Sexual Behavior in Young Men: A Double-Blind, Placebo-Controlled, Cross-Over Study J. Clin. Endocrinol. Metab., June 1, 2004; 89(6): 2837 - 2845. [Abstract] [Full Text] [PDF]
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Y.-q. Gu, J.-s. Tong, D.-z. Ma, X.-h. Wang, D. Yuan, W.-h. Tang, and W. J. Bremner Male Hormonal Contraception: Effects of Injections of Testosterone Undecanoate and Depot Medroxyprogesterone Acetate at Eight-Week Intervals in Chinese Men J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2254 - 2262. [Abstract] [Full Text] [PDF]
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M. C. Meriggiola, A. Costantino, S. Cerpolini, W. J. Bremner, D. Huebler, A. M. Morselli-Labate, B. Kirsch, A. Bertaccini, C. Pelusi, and G. Pelusi Testosterone Undecanoate Maintains Spermatogenic Suppression Induced by Cyproterone Acetate Plus Testosterone Undecanoate in Normal Men J. Clin. Endocrinol. Metab., December 1, 2003; 88(12): 5818 - 5826. [Abstract] [Full Text] [PDF]
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S. von Eckardstein, G. Noe, V. Brache, E. Nieschlag, H. Croxatto, F. Alvarez, A. Moo-Young, I. Sivin, N. Kumar, M. Small, et al. A Clinical Trial of 7{alpha}-Methyl-19-Nortestosterone Implants for Possible Use as a Long-Acting Contraceptive for Men J. Clin. Endocrinol. Metab., November 1, 2003; 88(11): 5232 - 5239. [Abstract] [Full Text] [PDF]
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L. Turner, A. J. Conway, M. Jimenez, P. Y. Liu, E. Forbes, R. I. McLachlan, and D. J. Handelsman Contraceptive Efficacy of a Depot Progestin and Androgen Combination in Men J. Clin. Endocrinol. Metab., October 1, 2003; 88(10): 4659 - 4667. [Abstract] [Full Text] [PDF]
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G. F. Weinbauer, C.-J. Partsch, M. Zitzmann, S. Schlatt, and E. Nieschlag Pharmacokinetics and Degree of Aromatization Rather Than Total Dose of Different Preparations Determine the Effects of Testosterone: A Nonhuman Primate Study in Macaca fascicularis J Androl, September 1, 2003; 24(5): 765 - 774. [Abstract] [Full Text] [PDF]
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M. C. Meriggiola, T. M.M. Farley, and M. T. Mbizvo A Review of Androgen-Progestin Regimens for Male Contraception J Androl, July 1, 2003; 24(4): 466 - 483. [Full Text] [PDF]
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D. J. Handelsman Hormonal Male Contraception--Lessons from the East When the Western Market Fails J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 559 - 561. [Full Text] [PDF]
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Y.-Q. Gu, X.-H. Wang, D. Xu, L. Peng, L.-F. Cheng, M.-K. Huang, Z.-J. Huang, and G.-Y. Zhang A Multicenter Contraceptive Efficacy Study of Injectable Testosterone Undecanoate in Healthy Chinese Men J. Clin. Endocrinol. Metab., February 1, 2003; 88(2): 562 - 568. [Abstract] [Full Text] [PDF]
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, and group III 
(mean ± SEM). Letters represent significant changes, compared with baseline for group I (a), group II (b), and group III (c).
