Badaru Angela, Wilson Darrell M, Bachrach Laura K, Fechner Patricia, Gandrud Laura M, Durham Eileen, Wintergerst Kupper, Chi Carolyn, Klein Karen O, Neely E Kirk
Division of Pediatric Endocrinology and Diabetes, Stanford University, Stanford, California 94305, USA.
J Clin Endocrinol Metab. 2006 May;91(5):1862-7. doi: 10.1210/jc.2005-1500. Epub 2006 Jan 31.
Dosing of monthly depot leuprolide (DL) in central precocious puberty (CPP) varies considerably. U.S. practitioners use 7.5-15 mg, in contrast with the international standard of 3.75 mg. Pubertal suppression using the newer 3-month DL also has been reported from Europe. To date there have been no direct comparisons of these different DL doses.
In an open 12-month protocol, we tested the efficacy of three DL doses (7.5 mg- and 3.75 mg-1 month and 11.25 mg-3 month) given sequentially to subjects treated for CPP. Primary outcome measures were stimulated gonadotropin (Gn) levels at 12-wk intervals. The null hypothesis was no difference among doses.
Both existing and new patients with CPP received our standard therapy (DL 7.5 mg every 4 wk) for a minimum of 24 wk. In subjects with DL-stimulated LH 2 IU/liter or less, the dose was changed to 3.75 mg every 4 wk and evaluated 12 wk later. Subjects who met LH criteria (<4.5 IU/liter) on 3.75 mg then received a single dose of 11.25 mg-3 month and were reevaluated 12 wk later. Serum LH/FSH and sex steroids were obtained 40 min after DL injection.
Thirty subjects were enrolled (20 naive; 24 girls, 6 boys), and 21 were evaluated on all three DL doses. DL-stimulated LH levels (mean +/- sd) were 1.30 +/- 0.74, 1.73 +/- 0.99, and 2.13 +/- 1.41 on 7.5 mg, 3.75 mg, and 11.25 mg-3 month, respectively (7.5 vs. 3.75 mg, P = 0.019; 7.5 mg vs. 11.25 mg-3 month, P = 0.004, Wilcoxon ranked sign test). Mean FSH levels were 2.86 +/- 1.91, 3.91 +/- 1.98, and 3.96 +/- 1.34, respectively (7.5 vs. 3.75 mg, P = 0.017; 7.5 mg vs. 11.25 mg-3 month, P = 0.020). No differences were detected in mean sex steroid levels.
Stimulated LH and FSH levels were significantly higher during therapy with both the 3.75 mg and 11.25 mg-3 month depot leuprolide doses, compared with 7.5 mg, contradicting the null hypothesis of no difference. These data suggest that low-dose 1- and 3-month DL preparations are associated with persistently greater gonadal stimulation in most CPP patients, but the LH/FSH results were not corroborated by differences in sex steroid levels. Whether various DL doses lead to long-term therapeutic differences remains to be determined.
中枢性性早熟（CPP）患者中，每月注射用亮丙瑞林（DL）的剂量差异很大。美国医生使用7.5 - 15毫克，而国际标准剂量为3.75毫克。欧洲也报道了使用新型3个月注射用亮丙瑞林进行青春期抑制的情况。迄今为止，尚未对这些不同的DL剂量进行直接比较。
在一项为期12个月的开放试验方案中，我们测试了依次给予CPP治疗患者三种DL剂量（7.5毫克 - 1个月、3.75毫克 - 1个月和11.25毫克 - 3个月）的疗效。主要结局指标是每隔12周刺激后的促性腺激素（Gn）水平。无效假设是各剂量之间无差异。
新老CPP患者均接受我们的标准治疗（每4周注射7.5毫克DL）至少24周。对于DL刺激后促黄体生成素（LH）≤2国际单位/升的患者，将剂量改为每4周3.75毫克，并在12周后进行评估。在3.75毫克剂量下符合LH标准（<4.5国际单位/升）的患者，随后接受单次11.25毫克 - 3个月的剂量，并在12周后重新评估。在注射DL后40分钟采集血清LH/FSH和性激素。
共纳入30名受试者（20名初治患者；24名女孩，6名男孩），21名受试者接受了所有三种DL剂量的评估。7.5毫克、3.75毫克和11.25毫克 - 3个月剂量下，DL刺激后的LH水平（均值±标准差）分别为1.30±0.74、1.73±0.99和2.13±1.41（7.5毫克与3.75毫克比较，P = 0.019；7.5毫克与11.25毫克 - 3个月比较，P = 0.004，Wilcoxon秩和检验）。平均促卵泡生成素（FSH）水平分别为2.86±1.91、3.91±1.98和3.96±1.34（7.5毫克与3.75毫克比较，P = 0.017；7.5毫克与11.25毫克 - 3个月比较，P = 0.020）。平均性激素水平未检测到差异。
与7.5毫克相比，3.75毫克和11.25毫克 - 3个月注射用亮丙瑞林剂量治疗期间，刺激后的LH和FSH水平显著更高，这与无差异的无效假设相矛盾。这些数据表明，低剂量1个月和3个月的DL制剂在大多数CPP患者中与持续更强的性腺刺激相关，但LH/FSH结果并未得到性激素水平差异的证实。不同DL剂量是否会导致长期治疗差异仍有待确定。
