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National Research Institute for Family Planning (Y.-Q.G., G.-Y.Z.), Beijing 100081, China; Jiangsu Family Planning Research Institute (S.-H.W.), Jiangsu 210029, China; Hebei Family Planning Research Institute (D.X.), Hebei 050071, China; Yunnan Family Planning Research Institute (L.P.), Yunnan 650021, China; Henan Family Planning Research Institute (L.-F.C.), Henan 450002, China; Sichuan Family Planning Research Institute (M.-K.H.), Sichuan 610041, China; and Shandong Family Planning Research Institute (Z.-J.H.), Shandong 250002, China
Address all correspondence and requests for reprints to: Gui-Yuan Zhang, M.D., Department of Reproductive Endocrinology, National Research Institute for Family Planning, Beijing 100081, China. E-mail: zgyendan{at}public.east.net.cn.
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Abstract |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A new injectable formulation of T undecanoate (TU) in tea seed oil provides more stable long-term release of T into the circulation (7, 8). A preclinical study in long-term orchidectomized monkeys showed that injectable TU has more favorable pharmacokinetics and pharmacodynamics than TE (9). A clinical pharmacokinetic study showed that a single injection of this TU at doses of 500 or 1000 mg to hypogonadal men could maintain the serum T concentration within the normal range for at least 7 wk without apparent side-effects (10). A dose-finding study of TU for spermatogenic suppression demonstrated that monthly injection of either 500 or 1000 mg TU to normal Chinese men can sufficiently and reversibly suppress spermatogenesis without serious adverse effects (11). These promising pilot results prompted us to perform a larger multicenter clinical trial to further evaluate safety, contraceptive efficacy, and reversibility of this TU regimen in healthy Chinese men.
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Subjects and Methods |
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Three hundred eight normal healthy Chinese men, aged 20–45 yr, were enrolled into this study in six centers. Their female partners were between 18–38 yr of age. Based on the results of screening, all of the men had normal medical histories, physical examinations, and laboratory tests. All of them had basal sperm concentrations greater than 20 x 106/ml as well as serum gonadotropin and T levels within the normal range. Each man and his partner signed a consent form at the admission. The study and consent form were approved by ethics committee and institutional review board of the six participating centers and the Scientific and Ethical Review Group of the WHO Human Reproduction Program.
Androgen preparation
Injectable TU was provided by Zhejiang Xian Ju Pharmaceutical Corp. (Zhejiang, China). This TU preparation manufactured under the Chinese Pharmacopeia was available in ampoules containing 250 mg of the ester in 2 ml tea seed oil (Mellaleuca). The same batch of TU was used throughout the study.
Study protocol
This was a Phase II, open label, multicenter, contraceptive efficacy clinical trial consisting of a 2-month control period, a 12-month treatment period including 6 months for suppression and 6 months for efficacy, and a 12-month recovery period. From the beginning of the treatment period, all subjects were asked to provide a semen sample at monthly intervals by masturbation after 2–7 d of sexual abstinence and a fasting (at least 10 h after food intake) blood sample at 3-month intervals and to undergo general physical examination, including measurement of body weight, blood pressure, and andrological examination with inspection of external genitalia, measurement of testicular volume, and breast size and tenderness.
During the control period, the subjects were asked to provide two semen samples separated by a 2-wk interval; to provide a fasting blood sample for baseline routine hematology, hormone assays, and measurements of plasma lipids and chemistry; and to undergo a general physical examination and andrological examinations. The female partners were evaluated for their reproductive function at the admission.
During the suppression phase, an initial loading dose of 1000 mg TU (split 2-ml injection in each side of the buttocks), followed by 500 mg TU at monthly intervals were given until azoospermia or severe oligozoospermia was achieved, up to a maximum of six injections. Subjects entered into the efficacy phase once their sperm concentrations demonstrated azoospermia or severe oligozoospermia in two successive samples. Thus, the number of injections in the suppression phase varied from man to man due to differences among subjects in the time required for adequate spermatogenic suppression (most subjects received three or four injections). During the suppression phase, subjects used a barrier contraceptive. Research nurses from each center gave TU injections considering compliance with the study, recorded the injection date in the case report forms after each injection, and made an appointment for the next follow-up. A deviation of ±2 d was allowed for TU injections. Blood samples were drawn before the injections. Serum samples were allowed to clot for 24 h, were centrifuged, and thereafter were stored at -70 C until analysis.
During the efficacy phase, the study was divided into two arms. Subjects from three centers (Hebei, Henan, and Sichuan) received a maintenance dose of 500 mg TU at monthly intervals (short-term regimen), and subjects from the other three centers (Yunnan, Jiangsu, and Shandong) were administered 500 mg TU at 45-d intervals (long-term regimen) for 6 months. No other form of contraception except TU injection was used during the efficacy phase. The pregnancy rate was monitored by the Beijing Central Coordinating Center during the study. The efficacy phase ended after 6 months from the entry, at the time of discontinuation for sperm rebound, or withdrawal or discontinuation for any other reason, and subjects entered into the recovery period.
The recovery period commenced at the end of the efficacy phase. In this phase the sperm concentrations of the subjects were expected to return to their own baseline levels or normal reference value (sperm concentrations, >20 x 106/ml). At the beginning of the recovery period subjects were asked to switch back to their original or an effective contraceptive method if they wanted to avoid pregnancy. The recovery period terminated if the subject’s sperm concentration reached his baseline level or a normal reference value of more than 20 x 106/ml, with a maximum of 12-month duration.
Measurements
Semen analyses were performed according to the procedures outlined in the WHO laboratory manual for the examination of human semen and sperm-cervical mucus interaction (12). Azoospermia was defined as the absence of sperm from seminal fluid, even after centrifugation. Severe oligozoospermia was defined as sperm concentrations of 3 x 106/ml or less. Sperm rebound was defined as sperm appearing in the ejaculate after qualifying for entry into the efficacy phase with a concentration greater than 3 x 106/ml on two consecutive occasions, including a repeat examination at a 1- to 2-wk interval. Testis volume on both sides was estimated by Prader orchidometer, and measurements were combined as the total testis volume. Serum T, LH, and FSH were measured by commercial kits supplied by the Immunometrics Ltd. (London, UK) (13). The assay sensitivities were 0.35 nmol/liter, 0.1 IU/liter, and 0.2 IU/liter 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), and low density lipoprotein cholesterol were measured by method of phosphotungstic acid-magnesium precipitation; the normal ranges are 3.12–6.69, 0.42–1.37, and 1.50–4.88 mmol/liter, respectively.
Statistical analysis
Data processing included double input of the data in the programmed data bank, coding of accompanying illnesses, and any reasons for discontinuation. The cumulative life-table analysis (software package provided by WHO) was used to calculate primary and secondary failure rate, and cumulative continuation rate during the treatment period. Multifactorial and one-way ANOVA, followed by post hoc test (V8 software package, SPSS, Inc., Chicago, IL), were used to determine differences across time and phase for any parameter. Sperm concentration and LH and FSH data were log-transformed before analysis. Results are expressed as the mean ± SEM. P < 0.05 was considered significant. The end point of contraceptive failure was defined as when a subject’s partner became pregnancy or a subject’s sperm density rebounded during the efficacy phase.
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Results |
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Fifty-one subjects from Yunnan center were the first to be enrolled, and 48 subjects entered the efficacy phase with the long-term (45 d in between TU injections) regimen. From the second to third months of the efficacy phase, 4 subjects demonstrated sperm rebound. Therefore, the long-term regimen in Jiangsu and Shandong centers was discontinued, and the remaining subjects received a monthly regimen after approval by the ethics committees and institutional review boards of these two centers and the WHO. Thus, the long-term regimen has only been completely conducted at the Yunnan center.
Clinical features
Three hundred eight volunteers from six centers after screening were enrolled in the study. Nine men did not achieve azoospermia or severe oligozoospermia (their lowest sperm density was 4 x 106/ml) within the 6-month suppression phase and were classified as nonresponders. Thus, the primary failure rate of this regimen due to nonresponders was 2.9/100 couple years (95% confidence interval of 1.0–4.8/100 couple years). Three subjects withdrew from this phase. Three pregnancies occurred during the suppression phase due to failure or nonuse of a contraceptive method. The cumulative life-table analysis showed that 80% of subjects entered into the efficacy phase at the third month of the suppression phase. Because six of nine nonresponders were found in a single center (Yunnan), and they regularly drank some medicinal liquors, the same TU regimen and injection schedule, approved by local ethical committee, were conducted again in the same five of six subjects in Yunnan center after they stopped drinking medicinal liquor. Four of five subjects achieved azoospermia or severe oligozoospermia during the suppression phase. The remaining subject did not become oligozoospermic.
Two hundred ninety-six men entered into the efficacy phase at different time points of the suppression phase. Sixteen subjects including six men with sperm rebound withdrew from the efficacy phase, and the continuation rate during the efficacy phase was 95/100 couple years. Although subjects monthly received TU injections according to the scheduled protocol, sperm rebound occurred in six men during the efficacy phase; four of these received the long-term regimen. There was no pregnancy in partners of men who were persistently azoospermic or severely oligozoospermic during the 143.0 person years of the efficacy phase. One pregnancy was diagnosed in the partner of a man who demonstrated rebound. Therefore, the secondary failure rate of this regimen due to sperm rebound was 2.30/100 couple years (95% confidence interval of 0.5–4.2/100 couple years). The total failure rate of this regimen was 5.2%, and the efficacy rate was 94.8%.
Three pregnancies were diagnosed during the recovery period due to failure to use an acceptable contraceptive method after discontinuation of the TU injections.
No serious adverse effect or event occurred during the study. The most commonly reported side-effect was tenderness or discomfort in the injection sites lasting for 2 d. These side-effects occurred usually after one or two injections and then disappeared gradually. Acne occurred in 21 subjects after TU injections. Self-reported change in sexual desire varied among subjects, but the predominant response indicated an increase. No spontaneous complaints in mood or aggressive behavior were reported during the study period. All 308 subjects, except for 20 subjects who discontinued the study, completed follow-up through the recovery period.
The changes in body weight and total testis volume are shown in Table 1
. Mean body weight increased after TU injections, with a maximum increment of 4.8 kg at the suppression phase, but was stable thereafter. The mean body weight gradually decreased toward the baseline after cessation of TU injections. The decrement in total testis volume reached a maximum of 4.2 ml at the efficacy phase and then returned toward the baseline level during the recovery phase.
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The proportions of azoospermia and nonazoospermia during the first 6 months are shown in Fig. 1A. The proportion of azoospermic men gradually increased to 98% by the end of the efficacy phase (Fig. 1B). The proportion of categorized mean sperm concentration during the recovery period is shown in Fig. 1C. The monthly change in mean sperm density categorized by treatment and recovery with a log scale is shown in Fig. 2. The mean sperm density was progressively suppressed by TU injections. A significant reduction of spermatogenesis was first found by 1 month after the first TU administration. Mean sperm density during the efficacy phase was profoundly suppressed. Azoospermia or severe oligozoospermia was maintained for all subjects except those six subjects who demonstrated sperm rebound during the efficacy phase. Spermatogenesis started to recover after cessation of TU administration. Spermatogenesis in all subjects except those lost to follow-up returned to baseline or the normal reference range within the 12-month recovery period.
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The mean serum T concentrations increased significantly from the third month after TU injections compared with the baseline and were maintained at relative higher levels throughout the course of the treatment (Fig. 3). The mean serum T concentrations at the nadir value of 4-wk injection interval increased 131% after TU injections during the treatment period, but were still within the normal reference ranges. The mean T levels dropped to baseline levels by month 12. Significant suppression of both LH and FSH by TU injections was first found at month 3, and the nadirs of serum LH and FSH were found at month 9 compared with their baseline levels (Fig. 4). The mean serum LH and FSH concentrations decreased 72% and 70%, respectively, by TU injections during the treatment period and returned to baseline at month 12. There was no significant difference in the serum T, LH, and FSH levels between responders and nonresponders whereas serum LH and FSH were relative higher in those men who experienced sperm rebound during the efficacy phase.
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The mean HDL cholesterol levels decreased 14% during the treatment period compared with baseline. The mean maximal increments in total and low density lipoprotein cholesterol increased 14% and 26%; hemoglobin and hematocrit levels after TU injection increased 9% and 6%, respectively, during the treatment period compared with the baseline values. The changes in all parameters mentioned above remained within the normal reference ranges (Table 1
). These changes in lipids returned to the baseline values during the recovery period, whereas hematology parameters remained higher. Blood chemistry assessments of liver and kidney functions, evidenced by alanine amino-transferase, aspartate amino-transferase, glutamyl transpeptidase, blood urea, and serum creatinine, were within the normal reference ranges throughout the study.
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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 TU was 108 d, which is close to that of weekly TE injections. The mean time course to allow return of sperm production after cessation of treatment by TU was about 87 d, which is close to that required by other methods of male hormonal contraception (14). Four of six subjects with sperm rebound were found at the Yunnan center, which may be related to the long-term injection interval because of escape of LH and FSH inhibition. However, statistical analysis showed that there was no significant difference in body weight, testis volume, or reproductive hormones between subjects who experienced sperm rebound and those whose sperm concentrations were consistently suppressed below 3 x 106/ml.
There have been reports of nonresponders to TE or testosterone buciclate (TB) injections in non-Asian subjects (15, 16), whereas nonresponders to TE or TU injections were very uncommon in Chinese men. This is the first report of TU nonresponsiveness in Chinese men. Although there was a methodological (primary) failure rate of 2.9% and a secondary failure rate of 2.3% for this TU regimen, its total contraceptive efficacy was still superior to the first year failure rate of male condom use. In the WHO multicenter study evaluating the effectiveness of TE-induced oligozoospermia (<3 x 106/ml) and azoospermia, the pregnancy rates were directly related to the sperm concentrations during the efficacy period, when sperm concentrations were between 0.1–3 x 106/ml. Therefore, a sperm concentration of 3 x 106/ml was defined as a threshold for entry into the efficacy phase in this Phase II study. Although there were no pregnancies caused by men whose sperm density was less than 3 x 106/ml during the 6-month efficacy phase in this Phase II study, four pregnancies were diagnosed during the efficacy period when sperm density fell below this level in the WHO multicenter study. When the safety margin was further analyzed among those subjects with severe oligozoospermia during the efficacy phase in this Phase II study, it was almost 2-fold higher in subjects with sperm concentrations between 1.1–3 x 106/ml than in men with sperm concentrations between 0.1–1 x 106/ml during the early stage of the efficacy phase. In addition, sperm rebound during the efficacy phase of this Phase II study was highly related to sperm concentration between 1.1–3 x 106/ml. For these reasons, during a Phase III clinical trial of this regimen with large sample and a long-term efficacy phase, monthly monitoring of sperm concentration would be impractical. We suggest that the threshold to enter efficacy might be set at 1 x 106/ml to reduce the risk of pregnancy during the efficacy period in such an expanded study.
Weight gain was found in this study. The maximal increment in body weight during the suppression phase could be caused by an initial loading dose of 1000 mg TU, which may have exerted a more profound anabolic effect than the moderately elevated serum T levels after TU injections. In addition, because the peak serum T level was not monitored in this study, serum T levels measured during the treatment period of this study underestimated the intermediate T levels to which subjects were exposed. Thus, intermediate T levels presumably reached a supraphysiological level and prompted an increase in body weight and hemoglobin or hematocrit levels.
Unlike in previous clinical trial in Chinese men (11), HDL cholesterol was decreased during the treatment period compared with baseline values. It has been reported that TE can cause mild suppression of HDL cholesterol in Caucasian men (17, 18). A chronic lowering of the HDL concentration, particularly in an individual with low baseline levels, may be associated with an increased risk of coronary artery disease (17). Unlike the administration of TE, insertion of T pellet implants and administration of TB injections to normal Caucasian men did not decrease HDL cholesterol levels (16, 19). This finding of HDL cholesterol decrease during the treatment period, especially during the suppression phase, may relate to the supraphysiological peak serum T concentrations after an initial loading dose of 1000 mg TU, which could profoundly impact lipoprotein levels, compared with the more physiological and less fluctuating T levels produced by T implants or TB injections.
A significant increase in hemoglobin and hematocrit levels, although still within the normal range, was observed, as described in a previous TU study (11). A similar stimulation of erythropoiesis was reported when TE (15) and TB (16) were given to healthy men for contraception.
A large injection volume of TU (4 ml) administered at monthly intervals was concerned by some subjects during the treatment period. Recently, injectable TU has been further developed, and a greater depot effect has been achieved by using castor oil instead of tea seed oil as vehicle. This preparation allows longer injection intervals in the treatment of hypogonadism (20) and in contraceptive trials combined with progestin (21, 22) and would certainly be of advantage in further contraceptive trials in China.
In summary, monthly TU injections at a dose of 500 mg after an initial loading dose of 1000 mg can sufficiently suppress spermatogenesis in healthy, normal Chinese men without serious adverse effects. Sixteen subjects discontinued treatment, and only one pregnancy was described as a result of sperm rebound during the efficacy phase. The data demonstrate that the monthly administration of TU injections as a method of contraception for men results in a good continuation rate and a high level of service feasibility and contraceptive efficacy. As the TU injections may have potential benefits to increase lean body mass, muscle strength, and energy in some subjects, these men, particularly those in rural areas, wish to continue receiving TU injections for contraception. However, they do express a preference for a longer-acting regimen and less frequent collection of semen samples. Subjects who are willing to continue using TU injections also express concern about the long-term safety of using androgens. Based on the results from this study we proposed an expanded phase III clinical study in Chinese men to further assess long-term safety, contraceptive efficacy, and service feasibility of injectable TU in a larger population and over an increased duration of exposure. Such an expanded study would provide informative data for policy makers and service providers of family planning before any introduction of male hormonal contraception in China.
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Acknowledgments |
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Footnotes |
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Abbreviations: HDL, High density lipoprotein; T, testosterone; TB, testosterone buciclate; TE, testosterone enanthate; TU, testosterone undecanoate.
Received March 21, 2002.
Accepted October 8, 2002.
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, 0; 
, 0.1–1.0; 
, 1.1–3; 
, >3. B, Proportion of categorized mean sperm concentration (x106/ml) during the efficacy phase. Numbers in the parentheses indicate the absolute number of subjects at each time point. 
