Anawalt Bradley D, Amory John K, Herbst Karen L, Coviello Andrea D, Page Stephanie T, Bremner William J, Matsumoto Alvin M
Department of Medicine, University of Washington School of Medicine, Seattle, WA 98108, USA.
J Androl. 2005 May-Jun;26(3):405-13. doi: 10.2164/jandrol.04135.
The development of a safe, well-tolerated, effective, and reversible male hormonal contraceptive would be a major clinical advance for couples planning their family size and for control of population growth. High-dosage parenteral testosterone (T) esters alone or in combination with a progestogen (eg, depot medroxyprogesterone) have been shown to confer effective and reversible male contraception in clinical trials, but these regimens are associated with weight gain and suppression of serum high-density lipoprotein cholesterol (HDL) levels. We have previously demonstrated that intramuscular T enanthate 100 mg weekly plus oral levonorgestrel (LNG) 125, 250, or 500 microg daily suppresses spermatogenesis to levels associated with effective contraception, but there is a LNG-dosage-dependent effect of weight gain and HDL suppression. We hypothesized that intramuscular T enanthate 100 mg weekly plus a very low dosage of oral LNG would effectively suppress spermatogenesis in normal men without inducing weight gain or HDL suppression. We conducted a randomized trial comparing 6 months of intramuscular T enanthate (100 mg weekly) plus 31.25 microg of oral LNG daily (T+LNG 31; n = 20) or 62.5 microg of oral LNG daily (T+LNG 62; n = 21). The 2 regimens were equally effective in suppressing spermatogenesis to azoospermia, fewer than 1 million sperm/mL and fewer than 3 million sperm/mL (T+LNG 31 [60%, 85%, and 90%] vs T+LNG 62 [62%, 91%, and 95%] for azoospermia, fewer than 1 million and fewer than 3 million, respectively; P = NS). The T+LNG 31 group did not gain weight (0.25 +/- 1.08 kg; P = NS compared with baseline), but the T+LNG 62 group gained 2.5 +/- 0.77 kg (P < .05 compared with baseline). Serum HDL cholesterol levels declined significantly in both groups (percentage decline month 6 of treatment vs baseline: 12.0% +/- 2.6% and 15.1% +/- 3.0%; P < .05 for T+LNG 31 and 62 respectively). Serum low-density lipoprotein cholesterol levels also declined in both groups (percentage decline month 6 of treatment vs baseline: 6.9 +/- 3.9 and 6.0% +/- 4.1%; P < .05 for T+LNG 31 and P = NS for T+LNG 62). There were no clinically significant adverse events or significant changes in hematology or chemistry profiles in either group during the study. We conclude that 1) intramuscular T plus oral LNG has a very potent synergistic effect in suppressing spermatogenesis at LNG dosages equal to or lower than dosages used in common female oral contraceptive regimens and 2) large, long-term contraceptive efficacy trials should be conducted with a variety of androgen-progestogen combinations including long-acting T formulations such as depot T pellets or intramuscular T undecanoate plus depot LNG or very low dosage oral LNG.
开发一种安全、耐受性良好、有效且可逆的男性激素避孕药，对于计划控制家庭规模的夫妇以及控制人口增长而言，将是一项重大的临床进展。在临床试验中，单独使用高剂量的肠胃外睾酮（T）酯或与一种孕激素（如醋酸甲羟孕酮）联合使用，已被证明可实现有效且可逆的男性避孕，但这些方案与体重增加以及血清高密度脂蛋白胆固醇（HDL）水平受抑制有关。我们之前已证明，每周肌肉注射100毫克庚酸睾酮加每日口服125、250或500微克左炔诺孕酮（LNG）可将精子发生抑制至与有效避孕相关的水平，但存在与LNG剂量相关的体重增加和HDL受抑制的效应。我们推测，每周肌肉注射100毫克庚酸睾酮加极低剂量的口服LNG可有效抑制正常男性的精子发生，而不会导致体重增加或HDL受抑制。我们进行了一项随机试验，比较了6个月每周肌肉注射庚酸睾酮（100毫克）加每日口服31.25微克LNG（T+LNG 31；n = 20）或每日口服62.5微克LNG（T+LNG 62；n = 21）的情况。这两种方案在将精子发生抑制至无精子症、每毫升少于100万个精子以及每毫升少于300万个精子方面同样有效（T+LNG 31组无精子症、每毫升少于100万个精子以及每毫升少于300万个精子的比例分别为60%、85%和90%，T+LNG 62组分别为62%、91%和95%；P = 无显著性差异）。T+LNG 31组体重未增加（0.25±1.08千克；与基线相比P = 无显著性差异），但T+LNG 62组体重增加了2.5±0.77千克（与基线相比P < 0.05）。两组血清HDL胆固醇水平均显著下降（治疗第6个月较基线的下降百分比：T+LNG 31组为12.0%±2.6%，T+LNG 62组为15.1%±3.0%；T+LNG 31组和T+LNG 62组P均 < 0.05）。两组血清低密度脂蛋白胆固醇水平也有所下降（治疗第6个月较基线的下降百分比：T+LNG 31组为6.9±3.9，T+LNG 62组为6.0%±4.1%；T+LNG 31组P < 0.05，T+LNG 62组P = 无显著性差异）。在研究期间，两组均未出现具有临床意义的不良事件，血液学或化学指标也无显著变化。我们得出结论：1）肌肉注射T加口服LNG在LNG剂量等于或低于常用女性口服避孕方案所使用剂量时，对抑制精子发生具有非常强的协同作用；2）应进行大规模、长期的避孕效果试验，采用多种雄激素 - 孕激素组合，包括长效T制剂，如皮下埋植T丸剂或肌肉注射十一酸睾酮加皮下埋植LNG或极低剂量口服LNG。
