A New Steroid On The Market in the next few years

[lanky]

The synthetic steroid 7alpha-methyl-19-nortestosterone (MENT) is a potent androgen that is resistant to 5-reductase. It thus has decreased activity at the prostate and may have advantages over testosterone-based regimens in long term treatment or as part of a male contraceptive. Administration to eugonadal men results in suppression of gonadotropins, but its ability to support androgen-dependent behavior has not been investigated. For sustained release administration, MENT acetate was used, because its diffusion characteristics were more suitable for use in implants. However, upon release the acetate is rapidly hydrolyzed, and MENT is the biologically active moiety in circulation. We studied the effects of MENT on sexual interest and activity, spontaneous erection, and mood states in comparison with testosterone enanthate (TE) in 20 Caucasian and Chinese hypogonadal men recruited in Edinburgh and Hong Kong (n = 10 in each center). Outcomes were measured using a combination of daily diaries, semistructured interviews, and questionnaires. Nocturnal penile tumescence (NPT) was also recorded in the Edinburgh group. After withdrawal of androgen replacement treatment (wash-out phase) for a minimum of 6 weeks, subjects were randomized to two groups in a cross-over design. Drug treatment regimens were of 6-week duration and consisted of two implants, each containing 115 mg MENT acetate, inserted sc into the upper arm and removed after 6 weeks and two injections of TE (200 mg, im) 3 weeks apart. MENT treatment resulted in stable plasma MENT concentrations of 1.4 ± 0.1 nmol/L after 3 weeks and 1.3 ± 0.1 nmol/L after 6 weeks (mean ± SEM; all men). Nadir testosterone concentrations were 3.6 ± 0.6 nmol/L at the end of the wash-out phase and 9.4 ± 0.6 nmol/L 3 weeks after each injection. There were no differences in hormone concentrations between centers. There were no adverse toxicological effects.

There were only minor differences between the two treatments. Both MENT and TE treatment resulted in significant increases in sexual interest and activity, spontaneous erection (both by self-report and NPT measurement), and increases in positive moods, with decreases in negative moods in the Edinburgh group. In the Hong Kong group, both treatments increased waking erection, with a trend toward increased sexual interest and activity. Mood states appeared to be less affected during the wash-out phase than in Edinburgh men and showed no significant response to either treatment. These results demonstrate that MENT has similar effects on sexual activity and mood states as testosterone in hypogonadal men. As NPT is a physiological androgen-dependant outcome, these data provide further evidence for the androgenicity of MENT. The lack of detected effect of either androgen in Hong Kong men other than on waking erection illustrates the importance of the cultural context of symptomatology and its measurement. The appropriate dose of MENT remains to be determined, but these results support its development as a potential androgen replacement therapy.


Introduction
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Abstract
Introduction
Subjects and Methods
Behavioral assessment
Results
Discussion
References


ANDROGEN therapy is predominantly used for replacement in primary hypogonadism. Other potential indications include the treatment of secondary hypogonadism, particularly that associated with aging, and as a hormonal male contraceptive that will involve long term treatment of large numbers of healthy men (1). Recent developments in androgen administration (2, 3, 4, 5) have addressed some of the problems with previous preparations, but are all based on treatment with testosterone. The use of synthetic androgens allows the possibility of more specific effects tailored to particular indications. 7-Methyl-19-nortestosterone (MENT) is a synthetic androgen that is approximately 10 times more potent than testosterone in anabolic bioassays and as a suppressor of gonadotropin secretion, but it is resistant to 5-reduction. It therefore has relatively low potency in bioassays in which the testosterone-amplifying activity of 5-reductase is important, such as stimulation of prostate size in castrate animals (6, 7, 8). This may be an advantage in long term treatment (9). Human data on the androgenic effects of MENT are, however, currently limited to the demonstration of the ability of repeated injections to suppress gonadotropin secretion in normal men (10) and early studies of masculinizing effects in female breast cancer patients (11).

MENT is not bound by sex hormone-binding globulin and is cleared rapidly from the circulation (12). MENT acetate (MENT Ac) can, however, be prepared in the form of implants for subdermal insertion, thus giving the potential for long term replacement therapy or treatment. Although MENT has been demonstrated to restore sexual behavior in castrate male mice (13), there are no data on the ability of this steroid to provide androgen replacement in men. This study was therefore performed to assess the effects of MENT Ac-containing implants on sexual function and mood in hypogonadal men.


Subjects and Methods
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Abstract
Introduction
Subjects and Methods
Behavioral assessment
Results
Discussion
References


Subjects and treatments

Two groups of 10 hypogonadal men were recruited in Edinburgh, Scotland (all Caucasian), and in Hong Kong (all ethnic Chinese). Diagnoses were idiopathic hypogonadotropic hypogonadism (11 men), Kleinfelter’s syndrome (5 men), bilateral orchidectomy (2 men), following treatment for pituitary tumor (3 men), and cytomegalic adrenal hypoplasia (1 man). The mean age was 31 yr (range, 20–42) in the Edinburgh group and 38 yr (range, 28–47) in the Hong Kong group; the mean body mass indexes were 26 and 27 kg/m2 in the 2 groups, respectively (range, 21–35 in both groups). All men in the Edinburgh group and 7 in the Hong Kong group had received androgen replacement before recruitment; 3 men in the Hong Kong group had never previously received androgen replacement. All men were in good general health apart from their primary diagnosis, and hematological and biochemical analyses were normal. After recruitment, subjects entered an androgen wash-out phase of a minimum of 6 weeks for those receiving injectable or transdermal replacement therapy. The 2 men (both in the Edinburgh group) who were routinely being treated with sc testosterone pellets had subphysiological testosterone concentrations (<7 nmol/L) and showed symptoms of hypogonadism before entry to the study; testosterone pellets had been administered to these men 26 and 29 weeks previously. Plasma testosterone concentrations were in all men determined to be in the hypogonadal range (all <9 nmol/L) before starting MENT or testosterone enanthate (TE) treatment. The study was a randomized cross-over design with 2 6-week treatment phases comparing MENT with TE. Thus, in each center 5 men received MENT followed by TE, and 5 men TE followed by MENT. MENT treatment consisted of 2 implants containing MENT acetate inserted sc in the upper arm and removed after 6 weeks. The implants were prepared by the Population Council (New York, NY); each was 4.4 cm long and contained 115 mg MENT acetate, releasing 350–400 µg/day in vitro (Sundaram, K., unpublished data). Implants were inserted sc under the medial surface of the upper arm using a metal trocar with sterile technique under local anesthesia. Removal was also carried out under local anesthesia. Incisions were closed with sterile tape, and a bandage was applied for 24 h. TE treatment consisted of 200 mg TE (Primoteston, Schering AG, Berlin, Germany), im, repeated after 3 weeks to give a 6-week duration of treatment.

All men gave written informed consent before study entry, and ethical approval was granted from the local committees in Edinburgh and Hong Kong. The study was conducted according to good clinical practice guidelines under an approved Investigational New Drug license by the FDA.


Behavioral assessment
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Abstract
Introduction
Subjects and Methods
Behavioral assessment
Results
Discussion
References


Sexual activity, interest, and mood states were assessed by a combination of self-report in the form of daily diaries, semistructured interviews, and structured checklists.

Daily diaries (14) were completed throughout the study, starting a minimum of 3 weeks before the first androgen treatment. Information collected included erection on waking (full, partial, or none; scored 2, 1, and 0); occurrence of masturbation and sexual intercourse; overall level of the following moods during the day: cheerful, lethargic, depressed, energetic, or irritable; and interest in sex during the day. Moods and interest in sex were scored from 0 ("not at all") to 4 ("extremely"). To reduce the impact of treatment carryover, data were derived from the last 21 days of each treatment phase of the study. Diaries were translated into Chinese in Hong Kong.

Semistructured interviews, modified from the report by Cawood and Bancroft (15), were used to record the frequency of sexual intercourse and masturbation over the last 2 weeks of each phase of the study.

SES 2 is one scale of the Frenken Sexual Experience Scales (16). This measuring instrument has a substantial body of normative data and has been shown to have satisfactory psychometric properties. SES 2 (the psychosexual stimulation scale) refers to the extent that someone seeks or allows (rather than avoids or rejects) sexual stimuli of an auditory-visual or imaginary kind. Weighted scores were used, giving a mean score of zero for normative data as obtained by Frenken and Vennix. We have previously demonstrated a small increase in SES 2 when eugonadal men were treated with supraphysiological doses of testosterone (14); thus, it appears to be a useful measure of androgenic response in men. To avoid confusion we have reversed the sign of the score so that a high score means high allowance of sexual stimuli or higher psychosexual arousability. As the questions in this scale refer to noninteractional social-sexual situations, it is appropriate for a study population who do not all have current sexual partners.

Nocturnal penile tumescence (NPT)

NPT was measured in the Edinburgh group on 2 consecutive nights at the end of the androgen wash-out phase and at the end of each treatment phase. Recordings were carried out in the subject’s home using a Rigiscan device (Dacomed Corp., Bloomington, MN) as previously described (17). The first night was used to allow acclimatization, and the second night was used for data recording. Two subjects declined to use the device. The following measures were derived as defined by Carani et al. (18): total number of erections, number of satisfactory erections, maximum percent increase in circumference lasting more than 5 min, maximum percent rigidity lasting at least 5 min in any one erectile response, total time that the circumference increase was more than 30% from baseline, and total time that rigidity was more than 60%.

Blood sampling and hormone assays

Blood samples were obtained between 0730–1100 h. Serum testosterone was monitored during the wash-out phase to ensure that plasma concentrations were in the hypogonadal range before MENT or TE treatment. Further blood samples were obtained at the time of commencing the first treatment phase and at 3-week intervals thereafter. Samples were separated by centrifugation, and plasma was stored at -20 C until assay. Full blood count, clinical chemistry, and lipid analyses were determined by routine autoanalyzer.

Plasma concentrations of MENT and total testosterone were measured by RIA in the Steroid Research Laboratory, Institute of Biomedicine, University of Helsinki (Helsinki, Finland), as previously described (10, 19) for MENT and using WHO matched assay reagents for testosterone (20). All MENT measurements were derived from a single assay, and all testosterone measurements from each subject were also performed in a single assay. Because of cross-reactivity of testosterone (2%) and other serum factors in the MENT assay, the mean (±SEM) value obtained before MENT insertion (0.67 ± 0.03 nmol/L) was subtracted from values of samples taken during MENT administration. The intraassay coefficient of variation for MENT was 5% at testosterone concentrations below 5 nmol/L.

Statistical analyses

Average scores for waking erection, the five mood states, and interest in sex were calculated for the last 21 days of each phase of the study as recorded in the daily diaries. The frequencies of masturbation and sexual intercourse were calculated as proportion of days on which the sexual activity was recorded. As not all men had sexual partners, the data for masturbation and sexual intercourse were combined to give a measure of overall sexual activity, i.e. the proportion of days on which either sexual intercourse or masturbation took place. Overall sexual activity was similarly calculated from the semistructured interviews, although as these outcomes could have occurred more than once in a single day, they are not directly comparable with those obtained from the daily diaries.

The first stage of the analysis was to test for a difference between the two centers at Edinburgh and Hong Kong for all outcomes. As the distribution of the average scores was not always continuous and was often skewed, with a large proportion of men recording the same value, transformation to normality was not possible. Nonparametric tests (Mann-Whitney U test) were therefore used for all of the daily diary and semistructured interview outcomes. Population SES 2 scores have a normal distribution (16), and plots of our data did not suggest the contrary; parametric tests (two-sample t test) were therefore used.

Significant differences between the centers were found for some outcomes for the wash-out phase. Such differences will not invalidate the analysis due to the cross-over study design, as treatment comparisons are within subjects. However, if the change in behavior seen when comparing an outcome under treatment with that seen during androgen wash-out is related to the center, this would suggest that the data should not be combined and that analysis should be by center. As a significant center difference was found in several of the outcome measures, all analyses were performed separately for Edinburgh and Hong Kong.

For analysis of a cross-over study design, the period effect and interaction between period and treatment effect must first be found to be nonsignificant before testing for a treatment effect (all outcomes by Mann-Whitney U test, except SES 2 scores by two-sample t test). If this is not the case, e.g. if there are carryover effects, then a comparison should be made of only the first given treatment as two independent samples. It can be assumed that the period and interaction between period and treatment were not significant for any outcome if no mention is made of these tests in Results. Comparisons between the two treatments (MENT vs. TE) and between each treatment and the wash-out phase were tested by the Wilcoxon signed rank test for all outcomes, except SES 2, by paired t test.

Serum testosterone and MENT data were analyzed by t test.


Results
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Abstract
Introduction
Subjects and Methods
Behavioral assessment
Results
Discussion
References


Subjects and adverse events

Insertion and removal of the MENT Ac implants was well tolerated and was performed without complication in all cases. There were no withdrawals after recruitment in either center. There were no cases of abnormalities of blood cell count, clinical chemistry, or lipids (total cholesterol, high density lipoprotein, low density lipoprotein, or triglycerides) in any individual.

MENT and testosterone concentrations

MENT Ac administration resulted in significant increases in MENT concentrations at both 3 and 6 weeks over wash-out phase assay blank values (P < 0.001). Serum MENT concentrations were similar 3 and 6 weeks after administration (Table 1), indicating stable diffusion from the implant. Serum testosterone concentrations were increased during TE treatment, with similar concentrations at 3 and 6 weeks, and during MENTAc administration they were similar to those during the wash-out phase. There were no significant differences in concentrations of either hormone between the Edinburgh and Hong Kong groups at any time point. It should be noted that the concentration of testosterone measured during TE treatment is the nadir, 3 weeks after administration of TE.




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Table 1. Plasma concentrations of testosterone and MENT at each stage of the study




After removal, the amount of MENT acetate remaining in the implants was measured. From this, the average daily release rate was calculated to be 461 ± 55 µg/day·implant.
Sexual interest and activity

Daily diary scores for interest in sex increased during treatment with both androgens. However, there was evidence of a period effect in the Edinburgh group, i.e. there was a greater increase during the second treatment phase regardless of treatment order (P = 0.032). Further analysis was therefore confined to data from the first treatment phase. This demonstrated a significant increase in interest in sex with both MENT and TE in the Edinburgh group (both P = 0.043 vs. wash-out phase; Fig. 1a). There was also an increase during both treatments in the Hong Kong group, but this did not reach statistical significance.





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Figure 1. Effect of MENT and TE treatment on interest in sex as recorded in daily diaries (a) and SES2 score (b). Open columns, Wash-out phase; hatched columns, during MENT treatment; stippled columns, during TE treatment. Interest in sex is the daily score in the wash-out phase and the first treatment phase, as there was evidence of a period effect; thus, n = 10 for the wash-out phase, and n = 5/treatment. Data represent the median ± interquartile range. n = 10 for SES 2 score, which is given as the mean ± SD. *, P < 0.05; **, P < 0.02 [vs. wash-out phase, by Wilcoxon signed rank test (a) or paired t test (b)].




The SES 2 score increased during both treatments in the Edinburgh group (P = 0.010, MENT; P = 0.028, TE; Fig. 1b). SES 2 also increased during MENT treatment in Hong Kong (P = 0.033), but the increase during TE treatment in that center did not reach statistical significance. There were no significant differences between scores during MENT and TE treatment in either group, although the difference approached significance (P = 0.051) in the Hong Kong group.
Changes in sexual activity as recorded in daily diaries and structured interviews are shown in Fig. 2. In the Edinburgh group, the daily diaries showed a marked increase in frequency of masturbation (reaching statistical significance during TE treatment, P = 0.030) with a small increase in the frequency of sexual intercourse. There was a borderline significant increase in overall sexual activity in the Edinburgh group during both treatments (P = 0.050, MENT; P = 0.051, TE). There were no significant changes in the Hong Kong group. Data from structured interviews confirmed that the effect of treatment was more consistently seen in the Edinburgh group with significant increases in masturbation during MENT treatment (P = 0.017) and sexual intercourse with both androgens (P = 0.027, MENT; P = 0.034, TE). The frequency of masturbation was greater during MENT than TE treatment in the Edinburgh group (P = 0.041). Overall sexual activity was increased with both androgens (P = 0.012 for both treatments) in the Edinburgh group, whereas the increases in the Hong Kong group were not significant. One man in the Edinburgh group and two men in the Hong Kong group did not record any sexual activity in the daily diaries at any stage of the study, and only one man, in the Hong Kong group, did not record any in the interviews. Two and three men in the Edinburgh group and five and four men in the Hong Kong group recorded in the diaries no masturbation and no sexual intercourse, respectively, at any stage of the study. Corresponding numbers for the interviews were one and three men in the Edinburgh group and five and four men in the Hong Kong group. Figure 2 refers only to those men who did not have zero outcomes throughout the study, whereas the statistical analysis applies to both the full dataset of 20 men and to these subgroups of men, as the Wilcoxon test is not affected by unchanged scores.





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Figure 2. Effects of MENT and TE on sexual activity as derived from daily diaries (a) and structured interviews (b). For diary data, sexual activity was calculated as the proportion of days on which sexual activity (sexual intercourse and/or masturbation) occurred. For interview data, sexual activity was calculated as the average frequency per day. Data represent the median ± interquartile range. Open columns, Wash-out phase; hatched columns, during MENT treatment; stippled columns, during TE treatment. Diary data: Edinburgh group, n = 8, 7, and 9; Hong Kong group, n = 5, 6, and 8 for masturbation, sexual intercourse, and overall sexual activity, respectively. Interview data: Edinburgh group, n = 9, 7, and 10; Hong Kong group, n = 5, 6, and 9 for masturbation, sexual intercourse, and overall sexual activity, respectively. *, P < 0.05; **, P < 0.02 (vs. wash-out phase); , P < 0.05 (MENT vs. TE treatment; all comparisons by Wilcoxon signed rank test).




Waking erection and NPT
There was a significant increase in the waking erection score with both treatments (Fig. 3a). This increase was significant in both centers (P = 0.008 for both MENT and TE in both centers). There was a greater effect of MENT than TE in the Edinburgh group (P = 0.007, MENT vs. TE), but no difference between treatments in the Hong Kong group. Similar results were obtained when data were analyzed according to the proportion of days on which an erection was recorded.





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Figure 3. a, Effect of MENT and TE treatment on waking erection in the Edinburgh and Hong Kong groups; b—d, NPT data from the Edinburgh group. B, Total number of erectile responses and number of satisfactory erections; c, the total duration that there was an increase in circumference of more than 30% from baseline and the total duration that rigidity was more than 60% in minutes; d, the maximum percent increase in circumference and the percent maximum rigidity lasting at least 5 minin any one erectile response. Open columns, Wash-out phase; hatched columns, during MENT treatment; stippled columns, during TE treatment. Data represent the median ± interquartile range. n = 10 for waking erection in each group; n = 8 for NPT data. *, P < 0.05; ***, P < 0.01 (vs. wash-out phase); , P < 0.01 (MENT vs. TE treatment; all by Wilcoxon signed rank test).




NPT data was only obtained for the Edinburgh group. There were significant increases in the number of satisfactory erections, the total number of erections (TE only), the total time that the increase in circumference was more than 30% of baseline, the percent maximum rigidity lasting at least 5 min in any one erectile response, and the total time that rigidity was more than 60% (Fig. 3, b–d). There was no change in the maximum percent increase in circumference. There were no differences between the responses during MENT and TE treatment.
Mood states

There were significant differences between the Edinburgh and Hong Kong groups in three of the mood states at baseline, with the Edinburgh group scoring higher for depressed (P = 0.009) and irritable (P < 0.001) and lower for energetic (P = 0.005). Men in the Edinburgh group also scored more highly for lethargic and lower for cheerful, but these differences were not statistically significant. In the Edinburgh group, there were significant increases in the positive moods cheerful and energetic with both MENT and TE, and significant falls in the negative mood states depressed, lethargic, and irritable with both treatments (Fig. 4). There were no significant differences in any mood state between MENT and TE treatments. There were no significant changes in any mood state in the Hong Kong group with either treatment.





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Figure 4. Effect of MENT and TE treatment on mood states in Edinburgh (a) and Hong Kong (b) groups. Open columns, Wash-out phase; hatched columns, during MENT treatment; stippled columns, during TE treatment. Data are presented as medians and interquartile ranges. n = 10 in each group. *, P < 0.05; ***, P < 0.01 (vs. wash-out phase, by Wilcoxon signed rank test).





Discussion
Top
Abstract
Introduction
Subjects and Methods
Behavioral assessment
Results
Discussion
References


The implants used in this study contained 115 mg MENT Ac, each releasing 460 µg MENT Ac/day, which is then rapidly hydrolyzed into MENT. Based on the relative potency of MENT and testosterone and the daily production rate of testosterone (7, 21), it was decided to use two implants in this preliminary study. More detailed pharmacokinetic data of MENT release from similar implants have been obtained in a study of normal men (22), demonstrating zero order kinetics over 4 weeks. In that study, two implants resulted in plasma MENT concentrations similar to those in the present study, and profound suppression of gonadotropin and testosterone secretion. The present results are consistent with zero order release, although the limited blood sampling precludes more detailed analysis. Subsequent measurement of the amount of MENT Ac still present in the implants after removal was consistent with the measured in vitro rate of release and suggests that they could provide replacement for up to 8 months. The dose of TE used was chosen to be slightly lower than that routinely used in clinical practice, and measurement of plasma testosterone 3 weeks after each injection confirmed that it was starting to fall into the hypogonadal range. This minimized carryover into the second treatment phase for those men receiving TE first in a dose previously demonstrated to improve mood state in hypogonadal men (23). Complete restoration of both sexual interest and moods occurs at testosterone concentrations below the laboratory normal range (23, 24, 25). Behavioral and physiological (NPT) analyses were confined to the second 3 weeks of each treatment phase to further minimize carryover effects.
Effects on sexuality

Although the overall effects of this study demonstrate convincingly that MENT is as effective as testosterone in reversing the effects of androgen withdrawal on aspects of sexuality, a number of differences between the two centers were observed. These were not confined to the effects of MENT and are of potential relevance to androgen effects in general. Given that the two centers in this study were situated in contrasting cultural contexts and that this is the first published study of such androgen effects involving a setting that is not in North America or Europe, these center differences are interesting and of potential importance.

Probably the most robust physiologically direct effect of androgens in the human male that is relevant to sexuality is the effect on spontaneous erections during sleep (NPT). A dose-response relationship between androgen replacement and waking erection (i.e. the last NPT of the night) has been demonstrated (25, 26), and androgen replacement increases the magnitude of NPT (24, 25, 27, 28). These effects are not secondary to changes in sleep patterns (25, 27). In this study a clear effect of both androgens on waking erection was observed in both centers, and this effect was further validated in the Edinburgh group by the predicted effect on NPT recorded during sleep. Therefore, in this direct physiological effect, no center differences were observed.

Sexual interest was measured in two ways, by a five-point daily rating and by the SES 2 questionnaire scale. Both measures showed a clear, significant effect in the Edinburgh group and a weak, mostly nonsignificant effect in the Hong Kong group. Similar center differences were found for overall sexual activity. In general, the effects of androgens on sexual activity have been less consistent across studies than the effects on sexual interest or NPT. However, the main type of sexual activity to increase with androgen replacement in the Edinburgh group was masturbation, reflecting the variable possibility for sexual activity with a partner in these hypogonadal men. Furthermore, it was in rates of masturbation during androgen replacement rather than partnered sexual activity that the Hong Kong men were most markedly different, with half the men in Hong Kong recording no masturbation at any stage of the study. This could well reflect a cultural difference in the acceptability of masturbation. The impact of the Ying Yang doctrine on Chinese culture, for example, encourages sexual abstinence as a way of achieving or maintaining higher levels of strength and vitality (29). This raises the issue of the cultural appropriateness of the measures used.

Effects on mood

In general, effects of androgen withdrawal and replacement on mood are less consistent than the effects on sexuality. Some studies have shown a beneficial effect of testosterone on mood in hypogonadal men (23, 25, 30, 31); others have not (26, 32). In the present study there was a clear center difference in this respect, mainly manifested as a difference in mood states during the androgen withdrawal phase. The Edinburgh men reported more depression, irritability, and lethargy and less energy and cheerfulness than the Hong Kong men during this phase. As a result, there was greater potential for improvement in mood states during androgen replacement in the Edinburgh group, and that was shown to be the case; the Hong Kong men did not change. It is questionable whether the effects of androgens on mood variables, with the possible exception of energy, are a direct physiological effect. They may depend more on psychological interpretation of the actual physiological effects that occur (e.g. how does one feel about being less sexually interested?). If that is the case, we would not only expect to find more variance in mood effects in general, but also the potential for cultural differences. For example, in a recent study of women from Edinburgh and Manila, Philippines, we found that the Edinburgh women reported more negative mood around menstruation than the Manila women, who were more likely to report certain physical symptoms, such as backache (33). Thus, we may not have been asking the right questions of the Hong Kong men in this study. Clearly, if androgens such as MENT are to be used widely and in different cultures, it is important that the apparent cultural differences identified in this report be further studied.

MENT can be converted by aromatase to an active estrogen, 7-methyl estradiol (34), but it is resistant to 5-reductase (6). The effects of MENT may thus in part reflect those functions of testosterone that are mediated by estrogen receptors, but to a lesser degree those functions that involve amplification by 5-reductase. The metabolism of testosterone is important in mediating its effects in several physiological systems, including aromatization in the control of gonadotropin secretion (35) and 5-reduction in the prostate (36). 5-Reductase is also present in the human brain (37); however, the isoform present in cerebral cortical tissue is type I rather than type II, which predominates in reproductive tract tissues (38, 39, 40). Although it is clear that testosterone is necessary for normal sexual function (41), the role of aromatization or 5-reduction in humans is uncertain (42, 43, 44). In castrate male rodents, MENT fully restores sexual behavior (45, 46), but does not restore aggressive behavior, in contrast to testosterone, which restored both (13). Effects on libido and potency were reported by only small numbers of men during administration of the 5-reductase inhibitor finasteride for treatment of benign prostatic hyperplasia (47); however, that drug has selectivity for the type II isoform not detected in human cerebral cortex (39, 40). The demonstration here of the effectiveness of MENT in restoring sexual function and mood in hypogonadal men provides indirect evidence that 5-reduction is not required for mediation of the influence of testosterone on these behaviors in men.

In conclusion, these results demonstrate that MENT is able to provide physiological and behavioral androgen replacement in hypogonadal men. MENT was demonstrated to have effects on two groups of hypogonadal men from different ethnic backgrounds, confirming the validity of the data. There were only minor differences between the responses to MENT and to conventional testosterone replacement therapy using a range of outcome measures, but the appropriate dose for this or other clinical indications remains to be established. MENT may therefore provide effective replacement therapy with a degree of selectivity at different androgen-responsive sites

 

[Stacemranger]

That's a lot to read. I read some of it. Didn't really understand it.

 

[lanky]

basicly nandrolone that wont deactivate as easily and does not overstimulate the prostate..

 

[CO B-man]

basicly nandrolone that wont deactivate as easily and does not overstimulate the prostate..

Wow! Thanks for that I can barely read a story in readers digest without losing concentration let alone a book! LOL! Thanks for the post!

 

[OMEGA]

Your a good bro lanky

 

[FISHTALES]

Your a good bro lanky

agreed!

 

[lanky]

and roughly 10 times more anabolic than test....sounds like the futue will be promising for AAS...they are currently studying this steroid as a contraception for men, and as a Hrt for older men because no overstimulation of the prostate.

 

[doublefister]

is there a link for this somewhere?

 

[lanky]

is there a link for this somewhere?

http://jcem.endojournals.org/cgi/content/full/84/10/3556

 

[lanky]

more on this chemical in trials for male contraception..

Several preparations of testosterone and its esters are being investigated alone or in combination with other gonadotropin-suppressing agents as possible antifertility agents for men. We studied the effectiveness of 7alpha methyl-19-nortestosterone (MENT) as an antispermatogenic agent in men. MENT has been shown to be more potent than testosterone and to be resistant to 5-reduction. For sustained delivery of MENT, we used a system consisting of ethylene vinyl acetate implants containing MENT acetate (Ac), administered subdermally. Thirty-five normal volunteers were recruited in 3 clinics and were randomly assigned to 1 of 3 doses: 1 (12 men), 2 (11 men), or 4 (12 men) MENT Ac implants. The initial average in vitro release rate of MENT Ac from each implant was approximately 400 µg/day. Implants were inserted subdermally in the medial aspect of the upper arm under local anesthesia. The duration of treatment was initially designed to be 6 months. However, in 2 clinics the duration of treatment was extended to 9 months for the 2-implant group and to 12 months for the 4-implant group. Dose-related increases in serum MENT levels and decreases in testosterone, LH, and FSH levels were observed. Effects on sperm counts were also dose related. None of the subjects in the 1-implant group exhibited oligozoospermia (sperm count, <3 million/ml). Four subjects in the 2-implant group became oligozoospermic, 2 of whom reached azoospermia. Eight subjects in the 4-implant group reached azoospermia, with 1 exhibiting oligozoospermia, whereas 2 were nonresponders. Side effects generally seen with androgen administration, such as increases in erythrocyte count, hematocrit, and hemoglobin and a decrease in SHBG, were also seen in this study and were reversible. Changes in lipid parameters were moderate and transient. Liver enzymes showed small changes. This study demonstrates that MENT Ac, when administered in a sustained release fashion via subdermal implants, can inhibit spermatogenesis over a prolonged period after a single administration and has the potential to be used as a male contraceptive.


Introduction
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References


THE DEVELOPMENT OF highly effective, practical, and acceptable nontraditional male contraceptives has proven to be a daunting challenge for more than 3 decades. Steroid hormones that inhibit gonadotropin secretion have been used in women for over 40 yr as contraceptives. Similar approaches are being investigated in men. Methods of fertility control in men that depend on the sustained suppression of gonadotropins will require the concomitant administration of an androgen as an essential part of the method. Results of a 1979 Population Council study (1) and two WHO studies conducted in the 1980s and early 1990s (2, 3) suggested that hormonal induction of azoospermia, but not oligozoospermia, could achieve contraceptive efficacy. Frequent injections of testosterone enanthate (TE) were used in the latter studies. To improve efficacy, new testosterone (T) formulations requiring less frequent administration are being tested alone or in combination with potent synthetic progestins or GnRH antagonists (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14).

7-Methyl-19-nortestosterone (MENT) is a synthetic androgen that is more potent than T for gonadotropin suppression and is resistant to 5-reduction, with potential advantages when used as a contraceptive (15, 16, 17). MENT acetate (Ac) has diffusion characteristics that are well suited for delivery via subdermal implants. MENT Ac is rapidly hydrolyzed in vivo to MENT, the biologically active molecule (18). Before undertaking this trial, the MENT implant system was studied in a 4-wk trial in normal men (17) and in a 6-wk trial in hypogonadal men (19). No adverse toxicological effects were observed in either trial, permitting initiation of the dose-finding trial described here.

This study examines the effect of one, two, or four MENT Ac implants on serum gonadotropins, sex hormones, and spermatogenesis in normal men.


Subjects and Methods
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Abstract
Introduction
Subjects and Methods
Results
Discussion
References


Subjects

A total of 36 normal men, 20–45 yr of age, were to be enrolled, 12 at each of 3 clinics with 4 men/clinic/treatment level. Before examinations and testing, volunteers gave written informed consent to randomization and to the schedule of tests, examinations, and related procedures. Volunteers judged as healthy by physical examination, medical history, clinical chemistry, and hematology; with 2 semen samples showing normal sperm counts; and having completed a short questionnaire concerning recent sexual history were eligible for participation. Volunteers with history of androgen use or hormonal therapy within the past 6 months, prostate disease, prostate cancer in first degree relatives, or abnormal findings on preentry laboratory screening or physical examination were excluded from the study.

Methods

MENT Ac implants were manufactured at The Population Council (New York, NY). Each implant is an ethylene vinyl acetate copolymer tube containing a central core that is a mixture of MENT Ac and silicone elastomer base. The ends of each tube are sealed with ethylene vinyl acetate polymer. Each implant was 4.9 cm long with a diameter of 2.66 mm. MENT Ac content ranged from 136.2–140.2 mg/implant. The initial in vitro release rate from a single implant was approximately 400 µg/day, decreasing over the course of a year to about 200 µg/d (our unpublished results). Levels of LH, FSH, T, SHBG, and prostate-specific antigen (PSA) were determined before treatment. Successful candidates were assigned subject numbers in chronological sequence of qualification for the trial and availability for implant placement. Contained in prenumbered, sealed envelopes, the randomly assigned implant sets were placed subdermally. Volunteers received one, two, or four implants, as determined by randomization lists. Insertion was through a trocar, after induction of local anesthesia with 2% lidocaine, in the medial aspect of the upper nondominant arm. All implants were inserted through a single incision, one at a time, and fanned out in a manner to keep them separated. For implant removal, local anesthesia was administered, and a small incision was made at the placement site; each implant was maneuvered to the incision site, and its end was grasped and removed. The procedures were similar to those used for female implant contraception (20).

Subjects or their partners were required to use an established method of contraception for pregnancy prevention. Adverse events and medications taken during the trial were recorded. Vital signs, blood pressure (BP), body weight, and sexual histories were recorded, and semen samples were analyzed. Volunteers provided samples of ejaculated semen monthly beginning on day 60 of treatment. Semen analyses were performed according to instructions in the WHO laboratory manual (21). Orchidometer or ultrasound was used to measure testes volume. Ultrasound was used to measure prostate volume in only one clinic (22). Hematology, clinical chemistry, PSA, SHBG, MENT, T, LH, and FSH were monitored at regular intervals. All hormone assays were performed centrally at the Steroid Research Laboratory, University of Helsinki. RIA for MENT and T used methods described, respectively, by Kumar et al. (23) and Sufi et al. (24). Time-resolved fluoroimmunoassay, using kits (DELFIA) from Wallace Oy (Turku, Finland) were used to measure FSH and LH. The limits of detection for MENT, T, LH, and FSH assays were 0.65 nmol/liter, 0.5 nmol/liter, 0.05 IU/liter, and 0.05 IU/liter, respectively. The intraassay coefficients of variation (CV) were 7.0%, 6.8%, 5.0%, and 3.4%, and the interassay CVs were 13.8%, 13.3%, 7.0%, and 4.9% for the same hormones. Local laboratories analyzed clinical chemistry, hematology, and PSA. Lipids were measured in fresh serum samples on the morning of blood collection. The subjects were advised to fast overnight. Data on sexual performance were obtained using a self-rating standard questionnaire (25).

In vivo MENT Ac release rate was estimated from recovered implants, following the extraction procedure described by Noe et al. (17). Monthly postremoval visits continued until sperm concentrations returned to 20 million/ml or higher. PSA, SHBG, MENT, T, LH, and FSH were monitored 1 month after removal. General physical and prostate examinations and testes volume measurements were scheduled 2 months after removal of implants.

Enrollment and modification of treatment and examination schedule

The treatment phase of the study was initially designed to be 6 months. However, enrollment time differed markedly at the three participating clinics, with clinic A (Munster, Germany) completing much of the study, while clinics B (Santiago, Chile) and C (Santo Domingo, Dominican Republic) were still recruiting subjects. Attainment of azoospermia in three of four men in the four-implant group at clinic A and the capacity of the multiple implant regimens to maintain substantial serum MENT levels at 6 months were very encouraging and led to modification of the protocol. With the aim of obtaining as much information as possible from this small study, the treatment period was increased in the two-implant regimen to 9 months and in the four-implant regimen to 12 months at clinics B and C. This protocol amendment took effect, however, after removal of all implants at clinic A. Enrollment was capped at a total of 35 individuals due to time constraints in recruitment. Hence, there were only 11 subjects in the two-implant group.

Ethical and regulatory considerations

The trial conformed to good clinical practice guidelines and the Declaration of Helsinki and had Investigational New Drug status from the U.S. FDA. Institutional ethics committees of the participating institutions approved the protocol and amendments. All subjects gave informed consent to participate in the study, and consents were obtained again in clinics where the study was extended. The Population Council conducted monitoring of the clinical studies.

Statistical analysis

The following statistical analyses were performed: descriptive statistics (Tables 1 and 2), two-way ANOVA including repeated measures ANOVA (Tables 3 and 4), ANOVA (Table 1 and Figs. 1 and 3), and Kruskall-Wallis ANOVA and median test (Fig. 2). McNemar tests were used to examine the significance of changes in frequencies of abnormal clinical chemistry values.




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TABLE 1. Selected characteristics of subjects at admission






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TABLE 2. Percentage of men achieving azoospermia and/or oligozoospermia during MENT Ac implant use






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TABLE 3. Mean values for hematology and lipids (all clinics)






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TABLE 4. Mean values for clinical chemistry (all clinics)







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FIG. 1. Serum MENT levels in subjects receiving one, two, or four MENT Ac implants. The study was amended to extend the duration of treatment to 9 months for the two-implant groups and to 12 months for the four-implant groups in two clinics. P1 denotes the 1 month posttreatment time point. Values are the mean ± SEM.







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FIG. 3. Serum levels of FSH (top panel), LH (middle panel), and T (bottom panel) in three groups of subjects treated with one, two, or four MENT Ac implants. Values are the mean ± SEM. P1 denotes the 1 month posttreatment time point.







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FIG. 2. Sperm concentrations (median and upper and lower quartiles) during treatment with one, two, or four MENT Ac implants. P1 and P2 represent 1 and 2 months posttreatment points. For months 3–6 the difference between doses was significant at P < 0.001, and at months 7–9 the difference between the two- and four-implant doses was significant at P < 0.01. Note that the concentrations shown as 0.001 were, in fact, azoospermic.





Results
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References


Subject characteristics at baseline
The characteristics of the subjects are presented in Table 1. At baseline no significant differences by dose group in physical indexes, sperm, or hormonal concentrations were found by two-way ANOVA. Several statistically significant differences among the clinics were detected by two-way analysis (Table 1).

Drug dosage levels

Sequentially scheduled serum assays of MENT and ex vivo extractions of MENT from used implants permitted independent estimates of the amount of drug received by the subjects. Serum MENT levels are presented in Fig. 1. Pretreatment values registered above zero because of cross-reactions with T and other molecules. Increases in measured MENT levels above baseline values were significant for each dose throughout the treatment period (P < 0.001), as were differences by dose (P < 0.001) in the first 6 months. At 6 months of treatment the mean increment over baseline in assayed MENT levels for the four-implant regimen was 85% higher than that of the two-implant regimen (P < 0.001); however, at 6 months MENT levels for the two lower doses did not differ statistically. At termination of treatment, the amount of drug remaining in the recovered implants was extracted, and the results were fitted to a nonlinear curve in the square root of time. The estimated average in vivo daily release rates of MENT Ac from each implant during 6, 9, and 12 months of use were 339, 277, and 240 µg/day, respectively.

Semen parameters

Sperm counts during the first 6 months of the study. Baseline sperm concentrations averaged 100.4 million/ml and did not differ by dose (Table 1). Mean sperm concentrations for all doses are shown in Fig. 2. During 6 treatment months, none of the 12 men in the 1-implant group ever reached oligozoospermia, defined as sperm counts less than 3 million/ml; mean sperm concentrations during treatment were never less than 60 million/ml in the 1-implant group.

Four subjects in the two-implant group achieved oligozoospermia (36%), with two of them (18%) exhibiting azoospermia during the first 6 treatment months (Table 2).

One subject in the four-implant group was discontinued from the study soon after initiation due to hypertension; hence, semen parameters were available from only 11 subjects in this group. Nine subjects (82%) exhibited oligozoospermia in the first 6 treatment months. All oligozoospermic men had counts of 100,000/ml or less for at least 2 months of treatment. Six months after treatment initiation 8 of these 9 had sperm concentrations less than 100,000/ml; the ninth subject’s count was less than 300,000/ml. Seven men (64%) at the highest dose achieved azoospermia at least once within the 6-month period. One other subject had multiple counts below 100,000/ml, including 1 count of 5,000/ml.

Findings of azoospermia or severe oligozoospermia in this group were not attributable to very recent sexual activity. During the first 6 treatment months only two subjects at this dose ever reported abstention of less than 3 days, and both men were repeatedly azoospermic at subsequent measurements with 3 or more days of abstention.

Sperm counts during extended treatment. Findings during the extended treatment period are presented in Table 2 and Fig. 2. No subjects in the single implant group continued treatment beyond the original 6-month schedule. Seven men with two implants received extended treatment through 9 months. One of the two subjects who had reached azoospermia continued to be azoospermic until month 7. None was oligozoospermic at month 9. In the four-implant group, six subjects continued through 12 months; five who were azoospermic maintained azoospermia until month 12. The other had a count less than 1 million/ml, which increased to 3.65 million/ml by the 12th month.

Over the entire study course, 2 (18%) of the 11 men with 2 implants became azoospermic, as had 8 (73%) of the 11 men with 4 implants. Median time to azoospermia was estimated to be less than 4 months in this group. Men with 4 implants were azoospermic an estimated 22% of treatment time in the first 6 months, but were azoospermic 79% of the time in the second 6 months.

Recovery of sperm counts. All subjects with one MENT Ac implant had sperm counts at or above 20 million/ml at 30 days posttreatment. Recovery time increased at the higher doses. Median time to recovery (20 million/ml) was about 3 months in the four-implant group. One subject at this dose, who had attained marked oligozoospermia, but not azoospermia, required 16 months to achieve a sperm count of 20 million/ml. No significant change in semen volume was noted during the study course.

Sexual performance

Little change during or after treatment was noted in four measures of sexual performance. The numbers of morning erections, unsustained erections, total erections, and ejaculations reported for the week preceding the clinic visit did not significantly differ from baseline means for any or all doses. The mean number of morning erections reported was 3.9 before treatment and 4.2 during the first 6 treatment months; reported total erections were 8.4/wk before treatment and 8.8 during treatment. Unsustained erections averaged 0.1/wk both before and during the initial 6 months of treatment for all subjects.

Physical changes during treatment and adverse events

Testes and prostate. Testicular volume was unaffected in the one-implant group during treatment. In the two- and four-implant groups, paired t tests indicated volume decreases at 6 months of treatment to 75% and 61%, respectively, of baseline means (P < 0.005 in each group). In men using four MENT Ac implants for a full year, testicular size decreased to 56% of the baseline volume. Two months after implant removal, testicular volume in the two- and four-implant groups had returned, respectively, to 88% and 86% of the mean pretreatment volume.

Prostate volumes by ultrasonography were measured only in clinic A. The volumes (mean ± SE) before treatment and at 180 days (end of treatment) were 21.7 ± 3.4 vs. 19.6 ± 2.0 for the one-implant group; 17.3 ± 1.2 vs. 16.1 ± 1.9 for the two-implant group, and 21.4 ± 1.0 vs. 18.4 ± 1.9 for the four-implant group. Although there was a decrease in prostate volume in all groups, the differences were not statistically significant (ANOVA). The prostate volumes showed some recovery at 240 days in all groups.

BP. BP measurements were taken for a maximum of 3 days in the month before treatment initiation. Randomization achieved statistically similar baseline systolic and diastolic BP for the three treatment groups, although baseline BP differed significantly by clinic (Table 1). During the first 6 treatment months, mean systolic BP increased by 4.8 (P < 0.05), as determined by repeated measure ANOVA. A smaller apparent increase in diastolic BP was not statistically significant. Neither systolic nor diastolic BP differed by dose during treatment.

Two men exhibited elevations of systolic and diastolic BP beyond the normal range. Each had levels of 140/90 mm Hg on the day of implant placement, but lower levels during screening. Subject A, who received a single implant, had a systolic BP of 150 mm Hg on days 30, 60, 90, and 180, but had levels of 120 and 140 mm Hg at the other two scheduled visits. In addition, the systolic level at 30 days postremoval was 160 mm Hg, but returned to normal at 60 days. This subject’s diastolic BP was 100 mm Hg on day 90, but was 70 or 80 mm Hg at all other times. Subject B received four implants. On day 30 his BP was recorded at 160/100 mm Hg. One week later it was 160/90 mm Hg. A follow-up visit next showed a BP of 140/100 mm Hg. A cardiologist recommended implant removal after a diagnosis of stage I–II hypertension. One month after implant removal, with dieting and cessation of smoking, the subject’s BP was 130/80 mm Hg.

Several other subjects who showed elevated BP sporadically had baseline readings below 135/85 mm Hg. Subject C had a single elevated systolic reading of 150 mm Hg on day 60. Subject D had systolic readings of 150, 160, and 150 mm Hg on days 90, 120, and 180, respectively. The 150-day visit was missed. Although his diastolic BP at baseline was 65, two readings of 90 mm Hg were recorded on days 60 and 120. Subject E showed a single high reading of 170/90 mm Hg on day 150. Subject F with a baseline diastolic reading of 75 mm Hg had readings of 95 mm Hg on days 30 and 90, and readings of 90 mm Hg on days 60 and 150. He had no abnormal systolic reading during treatment, but had a systolic reading of 140 mm Hg at the 30 day visit compared with a baseline of 115 mm Hg. At 30 and 60 days posttreatment, all subjects had normal diastolic BP. Two men had elevated systolic BP 30 days after removal, but both were normotensive 60 days postremoval.

Other adverse events. The most commonly reported adverse events were upper respiratory conditions, headache, and minor injuries. Several complaints related to the implants included pain and other reactions at the site, bruising at removal, long removal time, and multiple or long incisions for removal. Five men, at least one per clinic and one per dose, reported instances of impotence. There were also single reports of decreased libido, ejaculation failure, and premature ejaculation.

Discontinuation from the trial

Two men had implants removed before the scheduled date. One removal was the case of hypertension, discussed above. The second occurred early in the sixth month for personal reasons in a subject scheduled for removal at the end of 6 months; the subject returned for posttreatment evaluations.

Hormone levels

Serum MENT levels during treatment (Fig. 1) exhibited dose-related increases. Peak levels were seen at the initial 30-day postinsertion measurements. Mean MENT levels declined gradually thereafter until the end of treatment. Mean baseline levels of serum FSH, LH, and T did not differ among clinics or implant groups (Fig. 3). During treatment, significant dose-dependent decreases in FSH, LH, and T occurred with or without suppression of spermatogenesis. Men treated with four MENT Ac implants exhibited rapid and continued suppression of FSH, LH, and T and relatively rapid posttreatment recovery (Fig. 3). One of the two individuals in the high dose group who did not achieve oligozoospermia exhibited markedly less suppression of LH and FSH than the group as a whole, whereas the other subject’s hormone levels were similar to those of the group as whole.

Hematology, lipids, clinical blood chemistry, SHBG, and PSA

Hemoglobin and hematocrit showed small overall increases during treatment. Increased levels were largely confined to the highest treatment dose, which exhibited mean increases of 6–8% in hemoglobin and 6–10% in hematocrit levels (Table 3). Red blood cells increased significantly in the first 4 treatment months, rising 10% in men receiving four implants. By 1 month after removal, levels of these parameters fell back to or below pretreatment values. Other than a transient decrease in high density lipoprotein, there were no remarkable changes in serum lipid levels during treatment.

Most clinical chemistry parameters showed no remarkable changes during MENT use (Table 4). Significant decreases in the SHBG levels were seen in the two-implant group, whose starting levels were considerably higher than those in the other groups. PSA did not change significantly in any treatment group, remaining at the initial low levels in all subjects throughout the study (Table 4).


Discussion
Top
Abstract
Introduction
Subjects and Methods
Results
Discussion
References


As in the case of the 4-wk study (17), MENT Ac implants were well tolerated. In the present study 4 MENT Ac implants administered once were able to suppress spermatogenesis to a degree comparable to that reported in studies with multiple injections of TE or testosterone undecanoate (TU) or with T implants in normal men (2, 3, 4, 5, 10, 11, 12). With 1, 2, and 4 MENT Ac implants, 0%, 18%, and 82% of the subjects, respectively, achieved azoospermia, concomitant with a clear dose-dependent suppression of serum LH and FSH levels. In 1 WHO multicenter study (2), weekly im TE injections (200 mg) induced azoospermia in 65% of 271 men by 6 months. In a subsequent WHO study (3) weekly im injections of 200 mg TE induced severe oligozoospermia (<3 million/ml) or azoospermia in 98% of men. In a study by Handelsman et al. (4), 6 long-acting, biodegradable, T implants (1800 mg) elicited azoospermia in 5 of 9 (56%) men, whereas weekly TE injections (200 mg) induced azoospermia in 25 of 38 (66%) men. Severe oligozoospermia of less than 1 million/ml occurred in 100% of the implant group and in 97% of the TE group. Both treatments suppressed LH and FSH to undetectable levels. TU, a new depot preparation of a T ester that has more favorable pharmacokinetics than TE, is currently being investigated in many studies. In a study in Chinese men, 92% of 12 subjects receiving 500 mg TU, im, in tea seed oil and 100% of 12 subjects receiving 1000 mg TU, im, every 4 wk became azoospermic over a 16-wk treatment period (5). Kamischke et al. (10) showed that 1000 mg TU given im in castor oil every 6 wk, with or without levonorgestrel daily (250 µg, orally), over a 24-wk period induced azoospermia in nearly half of the subjects. Other studies by Kamischke et al. (11, 12) achieved greater sperm suppression with im TU (1000 mg, every 6 wk) plus either im norethisterone enanthate (every 6 wk) or daily oral norethisterone acetate (86–93% azoospermia). These results support findings in a large number of studies, suggesting greater suppression of spermatogenesis with a combination of progestins and androgens (9, 13, 14, 26, 27).

The median time to recovery to 20 million/ml (3 months in the current study) was similar to that observed in the WHO 1990 study.

After placement of the implants, serum MENT levels were highest at 1 month when the first measurements were made and then declined steadily. Serum gonadotropin levels were lowest at 1 month and remained well suppressed for up to 6 months. This was particularly evident in the high dose group despite the steady decline in serum MENT levels. This suggests that in the early months the subjects might have been exposed to supraphysiological levels of MENT. Relative to T, MENT has been shown to be 10 times more potent in suppressing gonadotropin levels in rats and monkeys (15, 28). It has been suggested that in men estradiol and T may be more important than dihydrotestosterone in the feedback inhibition of gonadotropins (29). As MENT does not undergo 5-reduction, it may maintain a greater ability to suppress gonadotropin secretion. A study with T implants in combination with a 5-reductase inhibitor (finasteride) showed no significant enhancement of spermatogenic suppression produced by T implants alone (30). In vitro studies with human placental microsomes have shown that MENT is aromatizable to 7-methyl-estradiol, a compound with higher affinity for estrogen receptors than estradiol (31). The extent of in vivo metabolism of MENT to an estrogenic compound and its role in the suppression of gonadotropins are not known at present.

In the current study there were some treatment-related increases in hemoglobin, hematocrit, and erythrocytes, which remained within the normal range. The hemopoietic effect of testosterone is well established and has been observed in other studies (4, 5, 11, 12, 32). This effect most likely results from a direct effect of androgens on the bone marrow. An increase in hemopoiesis has been reported with transdermal dihydrotestosterone gel also (33). It has been reported that T replacement in older men leads to increases in hematocrit and hemoglobin greater than those seen in younger hypogonadal men (34). In older hypogonadal men receiving T supplementation, the increase in hematocrit and hemoglobin was sufficiently high to be considered an adverse finding (35, 36). The long-term consequences of androgen treatment on hematological parameters in healthy men remain to be determined. At present, MENT is being investigated for use in young hypogonadal men for replacement therapy and in normal men for contraceptive purposes.

The clinical significance of elevated BP seen in some subjects in the current study remains unclear and will be further evaluated in ongoing studies. Elevations in BP have not been reported in studies with other androgens.

The higher than normal liver enzyme values noted sporadically were within the reference range and did not appear to be clinically relevant. No remarkable changes in lipid parameters were seen in the current study. A significant decrease in high density lipoprotein was noted only on day 60 in the high dose group. Some studies of androgens alone or in combination with progestins have reported some unfavorable changes in lipid parameters (3, 4, 11, 32). In contrast, a transdermal T replacement study in 65-yr-old men and a study in hypogonadal men did not indicate a deleterious effect on serum lipids (37, 38). A comprehensive review of the available literature suggests that the effects of androgens on atherogenic risk factors are unclear at present (39).

In the current study a significant decrease in mean testicular volume was observed in both the two- and four-implant groups. Significant reversible decreases in total testicular volume during treatment were also seen in other studies (5, 10, 11, 12). There was no significant change from baseline in semen volume, corresponding to the results of other studies using im TU with or without gestagens (10, 11). Prostate volumes measured by ultrasound at only one clinic were 10–17% lower on day 180 compared with the pretreatment values. The prostate-sparing effect of MENT has previously been shown in a study in castrated cynomolgus monkeys, where the effect of MENT was directly compared with that of T (28). In that study it was shown that a dose of MENT that was 10 times as potent as T in suppressing gonadotropins and maintaining body weight was only twice as potent in stimulating prostate volume. In other words, a dose of MENT that will completely replace T for its anabolic and antigonadotropic actions will be less stimulatory to the prostate. Hence, the use of MENT in men over the long term is expected to have health benefits. Serum PSA levels did not change in this study. Most studies of various preparations of T have not reported significant increases in PSA levels. However, in older men T supplementation led to sustained increases in PSA (38). In hypogonadal men T gel led to small increases in PSA in most subjects, with persistent elevated levels in a few subjects (39). The significance of the increase in PSA levels in older men and in young hypogonadal men on long-term androgen use for male contraception is not clear (40).

Maintenance of sexual behavior or functioning in this study, as determined from questionnaires, suggests that MENT Ac provided adequate androgen replacement while suppressing spermatogenesis and gonadotropins. Likewise, in studies by Kamischke et al. (10, 11) that included behavioral evaluation, sexual behavior during treatment was not altered. In a group of young hypogonadal men, the effect of MENT Ac implants on sexual behavior and mood was compared with that of standard TE injection replacement therapy over a 6-wk period using a cross-over study design. Based on standard questionnaires of mood, sexual interest, and spontaneous erections, it was concluded that MENT had effects similar to those of T (19) In a study in hypogonadal men, transdermal administration of T by gel and patches improved sexual function and mood (38).

In conclusion, these results indicate that MENT Ac, when administered via subdermal implants, can provide sustained levels of MENT, leading to a profound suppression of gonadotropins and inhibition of spermatogenesis. The findings also show that such implants provide effective levels of the compound for up to 1 yr. Most observed changes were similar to findings in earlier studies with other androgens. These results warrant further investigation of the use of MENT Ac implants with or without other agents for male contraception.