功能性下丘脑性闭经女性的骨密度：系统综述与荟萃分析。
完整摘要 · 中文译文
本研究旨在定量评估功能性下丘脑性闭经（FHA）女性的骨密度（BMD），确定不同骨骼部位的差异，并总结目前关于该人群骨健康受损诊断与管理的证据。方法：对采用双能X线吸收测定法（DXA）评估FHA或神经性厌食症（AN）女性与健康月经正常对照者BMD的比较研究进行了系统检索。共有11项研究符合纳入标准，其中5项被纳入荟萃分析。定量合成包括14组比较，腰椎和髋部BMD分别进行分析。采用Hedges' g及95%置信区间（CI）在随机效应模型下合并效应量。采用REML估计并结合Hartung-Knapp调整的敏感性分析及留一法分析评估合并估计值的稳健性。结果：11项研究的叙述性合成普遍显示，与健康对照者相比，FHA或AN女性BMD较低。在荟萃分析中，FHA女性的髋部BMD显著低于健康对照者（Hedges' g = -0.60；95% CI -1.13至-0.06；p = 0.030；I2 = 63%），而腰椎观察到中度降低（Hedges' g = -0.68；95% CI -1.48至0.13；p = 0.101；I2 = 83%）。在AN女性中，腰椎（Hedges' g = -1.66；95% CI -2.28至-1.04；p < 0.001；I2 = 71%）和髋部（Hedges' g = -1.37；95% CI -2.33至-0.42；p = 0.005；I2 = 89%）均观察到显著降低。 在敏感性和逐一剔除分析中，AN（神经性厌食症）患者的腰椎骨密度降低始终保持统计学显著性，是最稳健的发现；而FHA（功能性下丘脑性闭经）和AN两组髋部BMD（骨密度）估计值以及FHA组腰椎BMD的统计学显著性则对分析方法或剔除单项研究较为敏感。该系统评价表明，基于Z值解读的DXA（双能X线吸收法）仍是绝经前FHA女性骨骼评估的首选方法。建议在闭经≥6个月后评估骨骼健康，对于严重能量缺乏或有骨折史的女性应更早评估。恢复能量可用性、增加体重和恢复月经功能仍是治疗的基石。当闭经持续存在且确认BMD偏低时，生理性经皮17β-雌二醇联合周期性孕激素是首选的激素治疗，而不推荐将复方口服避孕药、双膦酸盐和地舒单抗用于常规管理。结论：功能性下丘脑性闭经与BMD降低相关，AN亚组观察到更为显著的骨骼缺损。这些发现支持对FHA女性尽早评估骨骼健康并及时纠正低能量可用性。研究间存在相当大的异质性以及部分合并估计值的敏感性，凸显了采用标准化诊断标准和统一骨骼结局指标开展更大规模前瞻性研究的必要性。
完整摘要 · 英文原文
This study aims to quantitatively evaluate bone mineral density (BMD) in women with functional hypothalamic amenorrhea (FHA), determine differences across skeletal sites, and summarise current evidence on the diagnosis and management of impaired bone health in this population. Methods: A systematic search of comparative studies evaluating BMD by dual-energy X-ray absorptiometry (DXA) in women with FHA or anorexia nervosa (AN) and healthy eumenorrhoeic controls was performed. Eleven studies met the eligibility criteria, five of which were included in the meta-analysis. The quantitative synthesis comprised 14 group comparisons, with lumbar spine and hip BMD analysed separately. Effect sizes were pooled using Hedges' g with 95% confidence intervals (CI) under a random-effects model. Sensitivity analyses using REML estimation with Hartung-Knapp adjustment and leave-one-out analyses were performed to assess the robustness of the pooled estimates. Results: The narrative synthesis of 11 studies generally showed lower BMD in women with FHA or AN compared with healthy controls. In the meta-analysis, among women with FHA, hip BMD was significantly lower than in healthy controls (Hedges' g = -0.60; 95% CI -1.13 to -0.06; p = 0.030; I2 = 63%), while a moderate reduction was observed at the lumbar spine (Hedges' g = -0.68; 95% CI -1.48 to 0.13; p = 0.101; I2 = 83%). In women with AN, substantial reductions were observed at both the lumbar spine (Hedges' g = -1.66; 95% CI -2.28 to -1.04; p < 0.001; I2 = 71%) and the hip (Hedges' g = -1.37; 95% CI -2.33 to -0.42; p = 0.005; I2 = 89%). The lumbar spine reduction in AN remained statistically significant across sensitivity and leave-one-out analyses and was the most robust finding, whereas the statistical significance of hip BMD estimates in both FHA and AN and of lumbar spine BMD in FHA was sensitive to the analytical approach or exclusion of individual studies. The systematic review demonstrated that DXA with interpretation based on Z-scores remains the preferred method for skeletal assessment in premenopausal women with FHA. Bone health assessment is recommended after ≥6 months of amenorrhea or earlier in women with severe energy deficiency or a history of fractures. Restoration of energy availability, weight gain, and recovery of menstrual function remain the cornerstone of treatment. When amenorrhea persists and low BMD is confirmed, physiological transdermal 17β-estradiol combined with cyclic progesterone is the preferred hormonal therapy, whereas combined oral contraceptives, bisphosphonates, and denosumab are not recommended for routine management. Conclusions: Functional hypothalamic amenorrhea is associated with reduced BMD, with substantially greater skeletal deficits observed in the AN subgroup. These findings support early assessment of bone health and timely correction of low energy availability in women with FHA. The considerable between-study heterogeneity and sensitivity of some pooled estimates highlight the need for larger prospective studies using standardized diagnostic criteria and uniform skeletal outcome measures.