Effects of T enanthate in normal men: experience from a multicenter contraceptive efficacy study* (1996)

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Objective: To evaluate the secondary impact of a prototype androgen contraceptive regimen on physical, metabolic, and behavioral variables.

Design: Prospective, open, noncomparative contraceptive efficacy study.

Setting: International multicenter study comprising 10 centers in seven countries.

Subjects: Two hundred seventy-one healthy men, age 31.8 ± 5.4 years (mean ± SD), range 21 to 45 years.

Interventions: Weekly 1M injections of 200 mg T enanthate.

Main Outcome Measures: Adverse effects and discontinuations; biochemical and hematologic changes and interpopulation differences.

Results: Chinese subjects were shorter and lighter and their baseline hemoglobin, plasma lipid, and liver enzyme levels were lower than in non-Chinese subjects. The most common side effects were painful injections, acne, fatigue, and weight gain. Gynecomastia and prostate problems were detected in 24 and 9 men, respectively, though no men stopped injections for such reasons. Testosterone enanthate increased body weight, hemoglobin, and urea but decreased testicular volume and creatinine. Plasma triglyceride, cholesterol, and low-density lipoprotein cholesterol were unchanged; high-density lipoprotein cholesterol decreased by 14% to 18% in non-Chinese but was unchanged in Chinese men. Liver transaminases were increased by 36% to 51% in Chinese but were unchanged in non-Chinese subjects. These T enanthate-induced effects were reversible within 6 months of stopping injections and were not related to the duration of T exposure.

Conclusions: Testosterone enanthate administration in a contraceptive trial produced significant but reversible effects on skin, muscle, liver, lipid metabolism, and hemopoietic functions that varied between population groups. These effects reflect the relatively high peak levels and fluctuations of plasma T produced by the weekly T enanthate regimen rather than an inherent feature of hormonal male contraception. The results highlight the need for long-acting preparations ofT with more stable delivery kinetics.




Testosterone Concentration

The regimen of 200 mg T enanthate every 7 days delivered an average daily dose of approximately 20 mg T. Total duration ofT exposure in this study was 2,720.3 man-months (1,000.4 man-months in Chinese and 1,719.9 man-months in non-Chinese centers) in the suppression and efficacy phases. The mean trough T level at 90 days was 44.7 ± 17.1 nmol or 132% (95% confidence interval [Cl] 118% to 146%) above baseline with no significant differences between Chinese and non-Chinese subjects. However, the mean increase from baseline levels after 180 days was higher in Chinese than in nonChinese subjects (182% versus 132%, P = 0.003) and similarly after 270 days (151% versus 115%, P = 0.02).


Complaints and Adverse Reactions

Fifteen subjects (eight during suppression and seven during efficacy) discontinued because of discomfort or pain at the site of injections (cumulative annual discontinuation rate of 7.5%). Other specific symptoms reported by the subjects are summarized in Table 2. A total of 80 subjects (29.5% of 271 recruits) complained of increased acne, predominantly of a truncal distribution affecting the shoulder and back, and/or increased oiliness of the skin at least once during T enanthate treatment. Of these, 32 subjects (40%) registered this complaint for the first time within 3 months and a further 33 (81.3% cumulative) after 6 months of T enanthate exposure. The acne was severe enough to warrant discontinuation from the study in nine subjects (all non-Chinese), three of whom required treatment with tetracycline (2) or isotretinoin with ultraviolet light (1). In the majority of subjects, acne resolved within 6 months of termination of treatment. Weight gain was reported by 10 non-Chinese men who remained in the study. However, two Chinese subjects complained of weight gain (3 and 5 kg) during the first 3 months of T enanthate treatment and discontinued for this reason. Twenty-two men (17 Chinese and 5 non-Chinese) remarked on increased fatigue and tiredness. One of these discontinued after 6 months. An increase in aggression was reported by seven subjects (all non-Chinese); three of these discontinued, one having received only one injection of T enanthate. Four non-Chinese men noticed cyclical changes in mood, one of these discontinued because of depression and increased libido. A decline in sexual interest was reported in four, but an increase was noted by eight subjects. Two men who experienced increased sexual interest also reported increased aggression and discontinued from the study because of the latter symptom. A decrease in testis size, increase in breast tissue, and disturbed sleep was reported by two, two, and three non-Chinese subjects, respectively, none resulting in discontinuation from the study. All symptoms resolved during the recovery phase.

Gynecomastia was detected in 24 non-Chinese subjects; 17 of these were from a single center. Thirteen subjects had detectable gynecomastia at the pretreatment examination before T enanthate treatment; 11 of these continued to have gynecomastia during treatment and/or recovery. Nine subjects apparently developed gynecomastia during T enanthate treatment and 2 developed it during recovery. No men stopped injections because of gynecomastia nor were any men treated for the condition.


There were nine observations of prostatic problems. One Chinese subject, who also complained of excessive tiredness and sleepiness, was reported to have acute prostatitis. Eight non-Chinese subjects, six from one center, were found to have prostatic abnormalities, which were described as "increased volume" (1), "slightly enlarged" (5), and no details provided (2). Two of these prostatic problems were recorded for the first time in the recovery period. The other six were reported during T enanthate treatment but not during recovery. None of these men stopped injections for this reason.

Similar levels of T before or during T enanthate administration were found in subjects who discontinued (Table 2) compared with the rest of the group or between those who discontinued for medical and nonmedical (personal-social or injection difficulties) reasons. Plasma T was not significantly different in those subjects reported to have acne or prostatic abnormalities compared with those who did not.


Changes in Physical Parameters

Serial percentage change from baseline in body weight, blood pressure, and testicular volume during T enanthate administration and recovery are shown in Figure 1A. Bodyweight increased by 3.6% ± 3.8% at 90 days and 5.0% ± 4.6% at 360 days. There was no significant difference between these two-time points to suggest a progressive effect ofT enanthate on body weight. After discontinuing treatment, mean body weight had declined significantly and was still slightly above baseline (+ 1.8%) by 180 days (Fig. 1A). There was no difference between Chinese and non-Chinese subjects in the percentage of weight gain. Systolic blood pressure increased persistently by 2.0% to 3.3% during T enanthate treatment but the increase in diastolic pressure was only significant at 180 days (2.7%) (Fig. 1A). These observed mean blood pressure increments were moderate and probably not clinically significant. One subject was discontinued from the study because of a persistently elevated diastolic blood pressure >95 mm Hg in the first 6 months of the study. Testicular volume decreased progressively with T enanthate treatment to a nadir of -19.5% of baseline in Chinese subjects by 360 days whereas non-Chinese subjects showed an abrupt decline at 90 days (-19.4% of baseline) and less of a decline between 90 and 360 days (-26.2% of baseline) (Fig. 2E). In both groups, testicular volume regained pretreatment dimensions by 180 days after discontinuing T enanthate (Figs. 1A and 2E).


Changes in Laboratory Measures

Hemoglobin and hematocrit increased by 7.6% and 6.4%, respectively, during T enanthate treatment and returned to baseline values by 90 days posttreatment (Fig. 1C, hematocrit not shown). Although the Chinese men showed only a modest «2.7%) but progressive rise, hemoglobin in non-Chinese men displayed a greater and more abrupt increase by 7.0% to 9.5% from 90 days (Fig. 2F). Two non-Chinese men were discontinued because of elevations in hematocrit >55%.

Blood urea decreased and creatinine increased reciprocally during T enanthate treatment (Fig. 1C). The changes were greatest during the first 180 days of treatment and reversed completely by 90 days post-treatment. There were no consistent differences between Chinese and non-Chinese subjects.

The aspartate and alanine aminotransferase enzymes showed marked population differences in response to exogenous T (Fig. 2C and D). Although these hepatic enzymes in non-Chinese subjects were unchanged throughout the study, increases of up to 36% for SGOT and 51% for SGPT were detected in Chinese subjects during T enanthate treatment. However, despite these rises, the absolute values of SGOT and SGPT remained within the physiological ranges. Insufficient hepatic enzyme data in the recovery phase were received from the three Chinese centers to confirm that these changes reversed, although there were no reports of clinical signs of liver damage. Mean r-GT levels were not changed significantly in either population during T exposure.


Serum triglyceride did not change significantly during the study (Fig. 1B). Total cholesterol decreased by 5% and 6% at 90 and 180 days of treatment, respectively. This predominantly represented changes in non-Chinese men because no significant changes in total cholesterol were observed in the Chinese subjects. Similarly, HDL cholesterol decreased only in non-Chinese subjects by 14% to 18% during T enanthate treatment (Fig. 1B and 2A). Two non-Chinese subjects discontinued from the study as a result of lowered HDL cholesterol levels. Low-density lipoprotein cholesterol did not alter significantly except at 90 days of treatment by -6% in nonChinese subjects (Fig. IB). The HDL: LDL cholesterol ratio was unaltered in Chinese subjects but showed a sustained reduction of 14% to 18% during T enanthate treatment in non-Chinese men (Fig. 2B)_ These lipid changes were fully reversible by 90 days after discontinuation of T (Fig. IB).




DISCUSSION

Suppression of spermatogenesis to a level compatible with adequate contraception through gonadotropin inhibition can be achieved only if endogenous T production also is reduced. Thus, T administration, for either physiological replacement to maintain extratesticular androgen-dependent functions or, as in the present study, for suppression of gonadotropins, is an indispensable component of a hormonal male contraceptive method.
Even though the unfavorable pharmacokinetics of weekly T enanthate injections make it an unlikely candidate as a future contraceptive androgen for men, the current data, being the largest available on the effects of exogenous T in normal men, present a unique opportunity to assess the effects of an androgenic ester on metabolic and other physiological functions_ They also provide a benchmark against which the secondary effects of other hormonal male contraceptive methods can be compared.




Testosterone Enanthate Regimen and T Concentration

Weekly 1M injections of 200 mg of T enanthate is a prototype regimen used in this study to examine the principle that hormonal suppression of spermatogenesis to azoospermia can provide effective and reversible contraception. The relatively short duration of action of T enanthate and its pharmacokinetic characteristics generate striking fluctuations in plasma T that necessitate a 7 -day injection interval to achieve adequate spermatogenesis suppression. Suppression of spermatogenesis therefore can be maintained only at the expense of accommodating repeated high peaks (and troughs) in T concentrations (5). After a single injection of 200 to 250 mg of T enanthate, plasma T concentrations peak 6 to 12 hours later, at concentrations 400% to 500% above baseline, followed by an exponential decline in the ensuing 10 to 14 days (6). Because of this fluctuation in T concentrations during the 7 -day injection interval, the 132% increase in preinjection plasma T underestimates the overall androgen exposure in the subjects.








The long-term pathophysiological consequences of the significant but reversible effects on the liver (transaminases and lipid metabolism), muscle, skin, and hemopoietic tissues during the administration of T enanthate in a contraceptive trial are currently unknown. However, they probably reflect the widely fluctuating and high peak levels of plasma T produced by the present prototype T enanthate regimen rather than an inherent feature of the overall hormonal approach to male contraception.
Now that the contraceptive efficacy of hormone suppression of spermatogenesis to azoospermia (1) and severe oligozoospermia (WHO Task Force on Methods for the Regulation of Male Fertility, unpublished data) is confirmed, the present results highlight the urgent need for long-acting preparations of T that can achieve stable plasma T levels over a prolonged period.
 

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