中藥對於提早發育女童減緩骨齡的療效：病例回溯性觀察研究

Abstract

研究背景與目的 性早熟女童(小於8歲出現乳房發育)因為過早及過多的荷爾蒙刺激使骨齡生長快速，進而壓縮成長時間而降低最終身高，提早發育的女童(8~10歲開始乳房發育)也會因為骨齡的增加而使預估身高無法達到遺傳身高，性早熟使用性釋素類似物(Gonadotropin-releasing hormone analogue, GnRHa)治療可有效增加預估身高，但提早發育在目前發表的研究中使用GnRHa或搭配生長激素(Growth hormone, GH)的療效仍有分岐，中藥對於性早熟女童也有減緩骨齡及降低荷爾蒙的療效，但對於提早發育女童中藥介入後療效的文獻量少，此研究希望探討使用GnRHa或中藥在提早發育的女童是否有延緩骨齡的作用。 研究方法 本研究採回溯性研究設計，分析2014/10~2020/10就診台北慈濟醫院兒童生長發育聯合門診的8~10歲提早發育女童，分為對照組(追蹤)，西藥治療(GnRHa)與中藥(TCM)治療，記錄和追蹤生長相關量測包含骨齡、預測身高、性荷爾蒙，以評估治療的臨床有效性，還收集包括實際年齡和出生體重在內的患者特徵。比較最終回診與初始狀態的生長量測值進行常規生長評估以及考慮到個體異質性的連續性觀察進行貝氏隨機效應模型來評估治療的有效性。 結果 本研究於6年研究期間共計納入140位(追蹤組31人，GnRHa治療組52人，TCM治療組57人)。三組就診收案時之平均年齡分別為8.75 歲 (sd=0.61，追蹤組)、9.57歲(sd=0.55，GnRHa治療組)，以及 9.23歲 (sd=0.59，TCM治療組)。三組之於就診收案時之骨齡量測分別為9.13歲(sd=0.87，追蹤組)、11.46歲(sd=0.77，GnRHa治療組)，以及10.18歲 (sd=1.08，TCM治療組)。三組完成療程時之平均年齡分別為10.31歲(sd=1.04，追蹤組)，11.37歲(sd=1.00，GnRHa治療組)，以及10.67歲 (sd=0.82，TCM治療組)。於完成療程後就診量測之骨齡則分別為11.24歲(sd=1.29，追蹤組)，12.35歲(sd=0.78，GnRHa治療組)，以及12.34歲(sd=1.10，TCM治療組)。前後預測身高的差異，GnRHa組增加2.10±2.40cm，TCM組減少1.00±2.91cm，追蹤組減少2.02±2.58cm (p<0.0001)。藉由貝氏線性混合模式進行治療對於骨齡之效益評估，調整第一次就診年齡後，相較於追蹤組，GnRHa和TCM組骨齡變化分別為-0.7251±0.0710, -0.2664±0.0673。 結論 中醫治療與GnRHa治療提早發育女童可達到顯著延緩骨齡以增加預測身高之治療效益。

Background Girls with precocious puberty (breast development under the age of 8) is associated with the reduction in final height as a result of early and excessive hormone stimulation that causes rapid bone age growth and a reduced growth time. Girls with early puberty (breast development at 8-10 years old) is also associated with the increase in bone age, which further results in the discrepancy between predicted height and target height (mid-parent height). Precocious puberty treated by using Gonadotropin-releasing hormone agents (GnRHa) therapy can effectively increase the predicted height. However, there are heterogeneities in the effectiveness of GnRHa related therapies administrated to girls with early puberty. As an alternative, Traditional Chinese Medicine (TCM) have been used to treat girls with precocious puberty to reduce sex hormones and to delay bone age. However, the effectiveness of TCM have barely been addressed. The aim of this research was thus to assess the effectiveness of TCM and GnRHa on bone age among the early puberty girls. Materials and Methods A retrospective cohort study was conducted to enroll the cohort of girls with early puberty aged 8 to 10 who visited Taipei Tzuchi Hospital Growth and Development Joint Clinic (GDJC) between October 2014 and October 2020. Three treatment modalities, observation with follow-up, GnRHa therapy, and TCM therapy, were provided to patients per protocol of GDJC. Information on growth related measurements including bone age, predicted height, and sex hormones were recorded and tracked to assess the clinical effectiveness of treatments. Patients characteristics including chronological age and birth body weight were also collected. The effectiveness of treatments was assessed by using the conventional approach of comparing the last growth profiles measures at last visit with that of baseline between treatments and also a series of Bayesian random effect models on successive observations of growth profiles taking into account the heterogeneities at individual level. Results A total of 140 patients were enrolled during the six-year study period (31 subjects in Control group, 52 subjects in GnRHa treated group, and 57 subjects in TCM treated group). The average chronological ages for three treatment groups at enrollment were 8.75 years (sd=0.61, control group), 9.57years (sd=0.55, GnRHa treated group), and 9.23 years (sd=0.59, TCM treated group), respectively. The average bone ages for three treatment groups at enrollment were 9.13 years (sd=0.87, control group), 11.46 years (sd=0.77, GnRHa treated group), and 10.18 years (sd=1.08, TCM treated group), respectively. The average chronological ages at completion of treatment course were 10.31 years (sd=1.04, control group), 11.37 years (sd=1.00, GnRHa treated group), and 10.67 years (sd=0.82, TCM treated group), respectively. The average bone age for three groups measured at the completion of treatment course were 11.24 years (sd=1.29, control group), 12.35 years (sd=0.78, GnRHa treated group), and 12.34 years (sd=1.10, TCM treated group). While the control group shows a reduction in the predicted height by 2.02±2.58cm compared with baseline value, the GnRHa treatment results in an increase by 2.10±2.40cm and the TCM treatment results in a reduction by 1.00±2.91cm (p<0.0001). By using a Bayesian linear mixed model, there was a significant deceleration in bone age for both treatment groups (GnRHa: -0.7251±0.0710, TCM: -0.2664±0.0673) compared with control group after the adjustment for chronological age at enrollment. Conclusion Both TCM and GnRHa treatments can effectively decelerate bone age for girls with early puberty to increase predicted height.