Handelsman D J, Conway A J, Boylan L M
Andrology Unit, Royal Prince Alfred Hospital, Sydney, Australia.
J Clin Endocrinol Metab. 1990 Jul;71(1):216-22. doi: 10.1210/jcem-71-1-216.
We studied the pharmacokinetics and pharmacodynamics of sc implanted pellets of fused crystalline testosterone. Three different regimens (6 x 100 mg, 6 x 200 mg; and 3 x 200 mg) were compared in a prospective, cross-over clinical trial in which androgen deficient men were administered the three-dose combinations in a randomized starting order at intervals of at least 6 months. Plasma free and total testosterone, sex hormone-binding globulin, LH, and FSH were measured before and at monthly intervals for at least 6 months after 111 pellet implantation in 43 men with hypergonadotropic (n = 22) or hypogonadotropic (n = 21) hypogonadism. Total and free testosterone levels peaked at the first month and were maintained at physiological levels for 4 to 5 (600 mg doses) or 6 (1200 mg dose) months after a single implantation. Absorption of testosterone from 100 mg and 200 mg pellets closely approximated zero-order throughout the effective life of the pellets and exhibited a half-duration of 2.5 months. The estimated rate of release of testosterone was 1.5 (95% confidence limits 1.3-1.6) mg/day.200 mg pellet as determined from direct measurement of residue in pellets recovered after extrusion and confirmed independently from percent absorbed-time plots. The bioavailability of testosterone was virtually complete and the time course was predictable from the total implant dose and, to a lesser extent, total initial surface areas of pellets. Despite wide fluctuations in testosterone, SHBG levels were not changed during 6 months. In men with hypergonadotropic hypogonadism, both LH and FSH levels were uniformly and markedly suppressed by increased testosterone after pellet implants. LH and FSH were highly correlated with each other (r = 0.87) and inversely with total (r = 0.47 and 0.45, respectively) and free (r = 0.46 and 0.47) testosterone levels. Nadir LH levels occurred at 1-3 months (600 mg) and 1-4 months (1200 mg) reaching levels comparable with eugonadal controls. In contrast nadir FSH levels occurred at similar times but remained elevated compared with eugonadal controls. We conclude that fused pellets of crystalline testosterone provides very satisfactory depot androgen replacement exhibiting many desirable features for androgen replacement.
我们研究了皮下植入的融合结晶睾酮丸剂的药代动力学和药效学。在一项前瞻性交叉临床试验中，比较了三种不同的给药方案（6×100mg、6×200mg和3×200mg），在该试验中，雄激素缺乏的男性以随机起始顺序接受这三种剂量组合，间隔至少6个月。在43例高促性腺激素性（n = 22）或低促性腺激素性（n = 21）性腺功能减退的男性植入111丸剂后，在植入前以及植入后至少6个月内每月测量血浆游离睾酮和总睾酮、性激素结合球蛋白、促黄体生成素（LH）和促卵泡生成素（FSH）。单次植入后，总睾酮和游离睾酮水平在第一个月达到峰值，并在600mg剂量组维持在生理水平4至5个月，1200mg剂量组维持6个月。在丸剂的整个有效寿命期间，100mg和200mg丸剂中睾酮的吸收几乎接近零级，半衰期为2.5个月。通过直接测量挤出后回收丸剂中的残留物确定，睾酮的估计释放速率为1.5（95%置信区间1.3 - 1.6）mg/天。从吸收百分比 - 时间图独立确认，200mg丸剂的睾酮生物利用度几乎完全，其时间进程可根据总植入剂量预测，在较小程度上也可根据丸剂的总初始表面积预测。尽管睾酮水平波动较大，但6个月内性激素结合球蛋白水平未发生变化。在高促性腺激素性性腺功能减退的男性中，植入丸剂后睾酮水平升高，LH和FSH水平均被一致且显著抑制。LH和FSH彼此高度相关（r = 0.87），与总睾酮（分别为r = 0.47和0.45）和游离睾酮（分别为r = 0.46和0.47）水平呈负相关。LH的最低点出现在1 - 3个月（600mg）和1 - 4个月（1200mg），达到与性腺功能正常对照相当的水平。相比之下，FSH的最低点出现在相似时间，但与性腺功能正常对照相比仍保持升高。我们得出结论，融合结晶睾酮丸剂提供了非常令人满意的长效雄激素替代，展现出许多雄激素替代所需的理想特性。
