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Original Studies |
-Methyl-19-Nortestosterone Maintains Sexual Behavior and Mood in Hypogonadal Men1
Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology (R.A.A.), Edinburgh, Scotland EH3 9ET; the Department of Obstetrics and Gynecology, Center for Reproductive Biology, University of Edinburgh (C.W.M., D.E., D.T.B.), Edinburgh, Scotland EH3 9ET; the Department of Medicine, University of Hong Kong (A.W.C.K., T.C.P., K.C.B.T.), Hong Kong; The Kinsey Institute (J.B.), Bloomington, Indiana 47405; and The Population Council, Center for Biomedical Research (K.S., A.J.M.-Y.), New York, New York 10017
Address all correspondence and requests for reprints to: Dr. R. A. Anderson, Medical Research Council, Reproductive Biology Unit, Center for Reproductive Biology, University of Edinburgh, 37 Chalmers Street, Edinburgh, Scotland EH3 9ET. E-mail: r.a.anderson{at}ed-rbu.mrc.ac.uk
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Abstract |
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-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.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsBehavioral assessmentResultsDiscussionReferences |
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-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.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsBehavioral assessmentResultsDiscussionReferences |
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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.
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Behavioral assessment |
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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.
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Results |
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TopAbstractIntroductionSubjects and MethodsBehavioral assessmentResultsDiscussionReferences |
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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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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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). 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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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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, 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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Discussion |
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TopAbstractIntroductionSubjects and MethodsBehavioral assessmentResultsDiscussionReferences |
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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.
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Acknowledgments |
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Footnotes |
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Received March 26, 1999.
Revised June 1, 1999.
Accepted June 9, 1999.
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References |
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K. K. Lee, N. Berman, G. M. Alexander, L. Hull, R. S. Swerdloff, and C. Wang A Simple Self-Report Diary for Assessing Psychosexual Function in Hypogonadal Men J Androl, September 1, 2003; 24(5): 688 - 698. [Abstract] [Full Text] [PDF]
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R. A. Anderson, A. M. Wallace, N. Sattar, N. Kumar, and K. Sundaram Evidence for Tissue Selectivity of the Synthetic Androgen 7{alpha}-Methyl-19-Nortestosterone in Hypogonadal Men J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2784 - 2793. [Abstract] [Full Text] [PDF]
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 R. A. Anderson and D. T. Baird Male Contraception Endocr. Rev., December 1, 2002; 23(6): 735 - 762. [Abstract] [Full Text] [PDF]
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T. Raivio, J. S. Tapanainen, P. Kunelius, and O. A. Janne Serum Androgen Bioactivity During 5{alpha}-Dihydrotestosterone Treatment in Elderly Men J Androl, November 1, 2002; 23(6): 919 - 921. [Abstract] [Full Text] [PDF]
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R. A. Anderson, D. Kinniburgh, and D. T. Baird Suppression of Spermatogenesis by Etonogestrel Implants with Depot Testosterone: Potential for Long-Acting Male Contraception J. Clin. Endocrinol. Metab., August 1, 2002; 87(8): 3640 - 3649. [Abstract] [Full Text] [PDF]
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D. Kinniburgh, H. Zhu, L. Cheng, A.T. Kicman, D.T. Baird, and R.A. Anderson Oral desogestrel with testosterone pellets induces consistent suppression of spermatogenesis to azoospermia in both Caucasian and Chinese men Hum. Reprod., June 1, 2002; 17(6): 1490 - 1501. [Abstract] [Full Text] [PDF]
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C. Wang and R. S. Swerdloff Should the Nonaromatizable Androgen Dihydrotestosterone Be Considered as an Alternative to Testosterone in the Treatment of the Andropause? J. Clin. Endocrinol. Metab., April 1, 2002; 87(4): 1462 - 1466. [Full Text] [PDF]
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 A. M. Matsumoto Andropause: Clinical Implications of the D |
, P < 0.05
(MENT vs. TE treatment; all comparisons by Wilcoxon
signed rank test).
