Abstract
The Chinese Expert Consensus on central precocious puberty (CPP) defines girls' rapid sexual development before age 8 as CPP; while after age 8 as early normal puberty (ENP). And the use of recombinant human growth hormone (rhGH) for CPP and ENP is off-label and lacks reliable evidence for clinical practice. This study only included girls due to the low prevalence among boys. We aimed to compare the long-term efficacy and safety of gonadotrophin releasing hormone analogue (GnRHa) in combination with or without rhGH for the treatment of CPP and ENP, and to explore the differences in the efficacy of different age of intervention. The medical information of girls with CPP or ENP at a women's and children's hospital from January 2013 to December 2018 was retrospectively collected. The primary outcome of efficacy was final adult height (FAH), and the secondary outcome included height gain, genetic height gain, standard deviation score of final adult height (FAHSDS), and standard deviation score of height (HSDS) gain. The safety outcomes were the rate of at least one adverse event of any type and the rate of each adverse event. We included factors with P < 0.05 in baseline analysis, and factors from systematic review and clinical experience as covariates in multivariable linear regression to adjust the clinical treatment choice, and subgroup analysis was taken to explore the efficacy of interventions at different ages. A total of 182 girls with CPP or ENP were finally included in this study. The adjusted results of multivariable linear regression showed that the mean(SD) of FAH in the combination therapy group (CG) (162.58 [0.46] cm) was higher than the monotherapy group (MG) (160.25 [0.35] cm) and the no treatment group (NG) (158.39 [0.47] cm) (P < 0.001), and the height gain(CG: 4.00 [0.46] cm, MG: 1.68 [0.36] cm, NG: - 0.18 [0.47] cm, P < 0.001), genetic height gain(CG: 6.18 [0.46] cm, MG: 3.85 [0.35] cm, NG: 1.99 [0.47] cm, P < 0.001), FAHSDS (CG: 0.66 [0.08], MG: 0.24 [0.06], NG: - 0.13 [0.08], P < 0.001), and HSDS gain(CG: 0.26 [0.08], MG: - 0.17 [0.06], NG: - 0.54 [0.08]) in CG were all higher than MG and NG. Besides, the incidence of at least one adverse event of any type in the CG was higher than MG and NG (CG: 83.30%, MG: 15.00%, NG: 16.70%, P < 0.001), among which the incidence of fasting insulin elevation (CG: 55.60%, MG: 1.25%, NG: 2.08%, P < 0.001) and hypothyroidism(CG: 44.4%, MG: 0.00%, NG: 0.00%, P < 0.001) was higher than the other two groups. Subgroup analysis indicated that, compared with the NG, the MG showed no differences in FAH in girls who entered puberty after the age of 8 years (1.46 [- 0.01, 2.93], P = 0.051) and those treated with GnRHa for less than 1 year (0.30 [- 1.34, 1.94], P = 0.718). Compared with the NG, there were no differences in FAH between the CG and MG (1.41 [- 0.76, 3.58], P = 0.204, 1.70 [- 0.77, 4.16], P = 0.178) in girls who initiated pharmacotherapy at the age of 10-12 years. Compared with the MG, the CG showed no differences in FAH in girls treated with rhGH in combination for less than 1 year (1.48 [- 0.09, 3.05], P = 0.064). The combination of GnRHa and rhGH can improve the FAH of girls with CPP and ENP to a certain extent, especially for those who began pharmacotherapy before 10 years of age and continued treatment for more than 1 year, but meanwhile increased the incidence of adverse events. The benefits, risks, and affordability of medication should still be comprehensively considered before decisions on pharmacotherapy.