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Original Studies |
Department of Endocrinology, National Research Institute for Family Planning (G.-y.Z), Beijing 100081, China; Population Center for Research in Reproduction, Department of Medicine, University of Washington, (Y.-q.G., W.J.B), Seattle, Washington 98195; Jiangsu Family Planning Research Institute, (X.-h.W.) Jiangsu 210029, China; and the Department of Endocrinology, Nanjing Medical University (Y.-g.C.), Jiangsu 210029, China
Address all correspondence and requests for reprints to: William J. Bremner, M.D., Ph.D., Department of Medicine, University of Washington, Box 356420, Seattle, Washington 98195. E-mail: wbremner{at}u.washington.edu
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A number of clinical approaches to male hormonal contraception with T esters given alone or in combination with additional gonadotropin-suppressive agents have been investigated (9, 10, 11, 12). In these studies weekly im injections of T enanthate (TE) were required for consistent suppression of gonadotropins and androgen replacement. Moreover, to attain physiological mean T levels, it is necessary to accept fluctuations in circulating T levels between injections, sometimes causing unwanted side-effects. These disadvantages hindered the acceptability of these regimens and highlighted the need for long acting preparations of T with more stable delivery kinetics. Crystalline T pellet implants that produce sustained elevation of serum T for 6 months and suppress gonadotropin levels were evaluated in clinical trials. When six 200-mg T pellet implants were administered to normal Caucasian men, the sperm concentration could be suppressed to a degree similar to that achieved by weekly TE injection (13). Drawbacks of the implant include the requirement for a surgical incision and the occasional spontaneous extrusion of an implant (which occurred in about 5% of subjects).
A new injectable formulation of TU in tea seed oil provides more stable long term release of T into the circulation (14, 15). Preclinical studies in long term orchidectomized monkeys showed that injectable TU has more favorable pharmacokinetics and pharmacodynamics (16) than TE, which is one of the most commonly used androgen preparations for treatment of androgen deficiency and for regimens of experimental male hormonal contraception (10, 17). A pharmacokinetic study in hypogonadal men demonstrated that mean serum T levels increased significantly from less than 10 to 47.8 and 54.2 nmol/L at the first week after a single dose of 500- and 1000-mg TU injections, respectively (18). Thereafter, serum T levels decreased progressively and reached the lower normal limit for adult men by days 50–60 without immediately apparent side-effects. In a prospective study on the efficacy of TU, at a dose of 500-1000 mg in combination with other drugs for treatment of 40 patients with aplastic anemia, no serious side-effects were found (19). These promising results prompted us to perform a clinical study of spermatogenic suppression with this injectable TU preparation. To define the effects of this injectable TU preparation this study aimed to determine the following. 1) Can the T ester alone uniformly suppress spermatogenesis? 2) Do the two doses of TU differ in effectiveness on spermatogenic suppression? 3) Are there detectable adverse effects?
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Subjects and Methods |
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Thirty-two normal Chinese men, aged 25–45 yr, were enrolled in this study. All of the men had normal medical histories, physical examinations, and screening laboratory tests. All of the men had basal sperm counts greater than 20 x 106/mL as well as serum gonadotropin and T levels within the normal range. The study and consent form were approved by the review board of the National Research Institute for Family Planning and the Jiangsu Family Planning Research Institute. Each man signed informed consent before beginning the study.
Androgen preparation
Injectable TU and placebo were provided by Zhejiang Xian Ju Pharmaceutical Corp. (Zhejiang, China). This TU preparation was available in ampules containing 250 mg of the ester in 2 mL tea seed oil. The same batches of TU and placebo were used throughout the study.
Clinical protocol
This was a double blind study consisting of a 4-week baseline period, a 16-week treatment period, and a 20-week posttreatment phase.
During the baseline period, all subjects were asked to provide 2–3 semen and fasting blood samples at 2-week intervals. The subjects were randomly divided into 3 groups: 1) 13 men received 500 mg TU injections, 2) 12 men were assigned to receive 1000 mg TU injections, and 3) 7 men received a placebo injection (tea seed oil only). One of the men in group 1 discontinued participation because of problems unrelated to TU administration.
During the treatment and posttreatment periods, subjects attended the clinic for physical examination and provided semen and blood samples at 4-week intervals. Subjects were asked to provide semen samples by masturbation after 3 days of sexual abstinence. Fasting blood samples were drawn before TU injections for analysis of hormone, plasma lipid, and chemistry parameters. Serum T levels therefore reflected the nadir (week 4) value. Each subject was given either TU or placebo im injections every 4 weeks until achieving two successive azoospermic ejaculates or until the end of the treatment period. The number of injections varied from man to man due to differences among subjects in the time required for spermatogenic suppression. Each subject received three or four injections; most received three injections. Serum samples were allowed to clot for 24 h and were centrifuged thereafter. All semen samples were stored at -70 C until analysis.
Measurements
Semen analysis was performed according to the WHO laboratory manual (20). Azoospermia was defined as the absence of sperm from seminal fluid, even after centrifugation. Severe oligozoospermia was defined as sperm counts 3 x 106/mL. Testis volume was estimated by Prader’s orchidometer. Serum T, LH, and FSH were measured by commercial kits supplied by Diagnostic Products (Los Angeles, CA). All samples from one subject were analyzed in a single assay. The assay sensitivities were 0.35 nmol/L, 0.1 IU/L, and 0.7 IU/L for T, LH, and FSH, respectively. The intraassay coefficients of variation for serum T, LH, and FSH were 5.1%, 3.7%, and 4.4%, respectively. The mean interassay coefficient of variation was less than 10% for all three hormones. Total cholesterol, high density lipoprotein (HDL) cholesterol, and low density lipoprotein (LDL) cholesterol were measured by PTA-magnesium precipitation; the normal ranges are 3.12–6.69, 0.42–1.37, and 1.50–4.88 mmol/L, respectively.
Statistical analysis
Cumulative lifetable analysis was used to show the dynamics of spermatogenetic suppression. This software package was provided by WHO. ANOVA with repeated measurements followed by post-hoc test or Bonferonni test were used to determine statistical significance within each treatment group across time and between the study groups, respectively. Results are expressed as the mean ± SEM. P < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean sperm concentrations of each group at baseline were
similar (Fig. 1
). The sperm concentration
in the two treatment groups was progressively suppressed by TU
injections, reaching a nadir by week 12. Significant suppression of
spermatogenesis by TU injections at both doses was found by week 4
compared with their baseline levels and the placebo group. There was a
tendency for spermatogenic suppression to occur more quickly in the
higher dosage group. Eleven of 12 subjects in the 500-mg TU group and
all subjects in the 1000-mg TU group achieved azoospermia. The man in
the 500-mg TU group who never achieved azoospermia became severely
oligozoospermic by week 12 (1 x 106/mL). After
cessation of TU administration, the sperm concentration in the both
treatment groups returned to the normal range during the recovery
period. The sperm concentrations in the placebo group remained
unchanged throughout the study.
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Mean serum T levels at baseline did not differ among the
groups (Fig. 2). There was a clear
dose-response relationship between the injected doses and serum T
levels. Mean serum T levels increased significantly in the higher dose
group at weeks 8 and 12 compared with those in the 500-mg and placebo
groups, but remained within the normal range. Mean T dropped to
baseline levels at week 16 because eight men in the higher dose group
and six men in the lower dose group received only three injections (the
last one at week 8, as they all had achieved azoospermia before the
last planned injection at week 12). Mean serum LH and FSH levels were
profoundly suppressed by both doses of TU to undetectable levels (0.1
and 0.7 IU/L for LH and FSH) at week 16 (Figs. 3 and 4).
Significant suppression of LH and FSH by both doses of TU was first
found at week 4 compared with their own baseline levels and levels in
the placebo group. The changes in serum reproductive hormones returned
to baseline levels by week 4 of the recovery period. Mean serum
reproductive hormones in the placebo group were stable within the
normal range throughout the study.
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The baseline levels of total, HDL, and LDL cholesterol were
similar among the groups (Table 1). Total
cholesterol did not show any significant differences between the
treatment and baseline periods. HDL and LDL cholesterol did not show
any significant differences within each treatment group across time or
between the treatment groups in any period of the study.
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Blood chemistry assessments of liver and kidney functions were within the normal reference ranges throughout the study and did not vary significantly with phase of the study.
Clinical features
Body weight increased in both dosage groups during the
treatment period compared with their own baseline levels and values in
the placebo group (Table 1
). No significant difference in body
weight was found between the two treatment groups. Body weight returned
to pretreatment levels during the recovery period. Total testis volume
(left and right) decreased significantly in all subjects in the two TU
groups during the treatment period compared with their own baseline
levels and values in the placebo group. No significant difference in
testis volume was noted between the two treatment groups. Testis volume
returned to the baseline during the recovery period. No changes in body
weight and testis volume were found in the placebo group.
A common report from subjects was discomfort in the injection sites lasting about 3–6 days, which then disappeared. Some subjects reported that TU injections stimulated their appetite. There was an occasional self-reported change in sexual desire, more commonly increased rather than decreased. No changes in aggressive behavior and mood states were reported.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The mean length of time required for achieving azoospermia by the two doses of TU was 12–16 weeks, which is close to that of weekly TE injections in Chinese men (21). However, TE in combination with CPA showed a more rapid onset of spermatogenic suppression in Caucasian men with a mean time course of 7–8 weeks (22). CPA is a synthetic steroid with potent progestational and antiandrogenic actions. CPA may interfere with androgen biosynthesis and action at the gonadal level (23, 24) and suppresses gonadotropins by acting synergistically with T. Another clinical study showed that TE in combination with an oral application of levonorgestrel also led to a rapid onset of spermatogenic suppression (25). Taken together, these results suggest the potential usefulness of a new regimen using injectable TU with oral CPA or levonorgestrel for shortening the time to spermatogenic suppression. The mean time course to allow return of sperm production after cessation of treatment by TU was about 16 weeks, which is close to that required by other methods of male hormonal contraception (12).
Serum T at the nadir value in both treatment groups was maintained at or above pretreatment levels during the treatment period. Because serum T at the peak value was not monitored in this study, serum T levels underestimated the integrated T levels to which subjects were exposed. Presumably, the integrated T levels reached a supraphysiological level, as there were increases in body weight and hemoglobin levels in the TU groups. Weight gain at both doses in this study was not as obvious as in the contraceptive efficacy trial of TE-induced azoospermia and severe oligozoospermia (21). The greater increase in body weight after TE injections could be caused by the higher serum T at peak value that may have exerted a more profound anabolic effect than the moderately elevated serum T levels after TU injections.
No change in serum levels of HDL, LDL, and total cholesterol was noted in any group between the treatment and baseline periods. Similarly, no significant changes in total, HDL, and LDL cholesterol were observed in Chinese men in the WHO multicenter study of TE administration. TE can cause mild suppression of HDL cholesterol in Caucasian men (26, 27). A lowering of HDL concentration, particularly in an individual with low baseline levels, might increase the risk of coronary artery disease (26). Unlike TE decreasing HDL cholesterol, T pellet implants and T buciclate injections to normal Caucasian men did not decrease HDL cholesterol levels (28, 29). This may be explained by supraphysiological T at peak values after TE injections that had greater impact on metabolic effects than the more physiological and less fluctuating T levels maintained by the T implants or T buciclate injections. A significant increase in hemoglobin, but still within the normal range, was observed in both treatment groups. A similar stimulation of erythropoiesis was reported when TE (30) and TB (29) were given to normal men for contraception. Our results suggest the TU preparation reported here can be developed as a male contraceptive in China with fewer biochemical effects on lipid and other metabolic parameters than are found with the currently available forms of T.
In the WHO clinical trial on contraceptive efficacy with weekly TE injections involving different ethnic groups, azoospermia could be achieved in only 45–70% of Caucasian subjects (10) compared with 88.9–100% of Chinese men. The explanation for this nonuniform induction of azoospermia remains unknown. There were no differences in a variety of endocrine parameters between men achieving azoospermia as opposed to oligozoospermia in response to weekly injections of TE (31, 32) or in the pharmacokinetics of the exogenous T (33). It has been hypothesized that low levels of residual androgens in the testes may allow the persistence of spermatogenesis. A recent clinical study using a combined regimen of the antiandrogenic progestin CPA and TE in Caucasian men showed very effective suppression of spermatogenesis. All 10 men in 2 dose groups became azoospermic, whereas only 3 of 5 men treated with TE alone achieved azoospermia. This finding suggests that not only can CPA act at the hypothalamic-pituitary level synergistically with T in suppressing gonadotropins evidenced by undetectable levels of LH and FSH by week 4 in all 10 subjects, but CPA, as an antiandrogen, could act at the gonadal level by competitively inhibiting the stimulatory effect of androgen from an endogenous or exogenous source (22). It has been recently reported that there was higher 5-reductase activity in men who failed to achieve azoospermia completely compared to that in men who achieved azoospermia when treated by TE weekly injections (34). It has been proposed that Chinese men might have less 5-reductase activity than Caucasian men, but there is a lack of direct evidence to support this hypothesis. A recent study demonstrated no significant differences in 5-reductase activity between Chinese men, whether living in China or the United States, and Caucasian counterparts living in the United States. Environmental/dietary, but not genetic, factors may influence androgen production and explain the differences between Caucasian and Chinese men (35).
In summary, this is the first dose-finding study of injectable TU for male contraception. Our results demonstrate that both dosages of TU administrated to normal Chinese men can sufficiently and reversibly suppress spermatogenesis without serious side-effects. These results suggest that these two dosages of TU could be used for evaluation of contraceptive efficacy in further studies.
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Acknowledgments |
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Footnotes |
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Received October 29, 1998.
Revised May 14, 1999.
Accepted May 21, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase activity in oligozoospermic men administered
supraphysiological doses of testosterone. J Clin Endocrinol Metab. 81:902–908.[Abstract]
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