Precision hormone therapy: identification of positive responders

Abstract

Since the introduction of menopausal hormone therapy (MHT) in the 1940s, randomized clinical trials and observational studies have been performed to determine the benefits and risks of MHT. However, MHT therapeutic impact remains under debate as multiple factors including genetic biomarkers and medical history contribute to inter-individual variations in neurodegenerative diseases. Herein, we review the characteristics of women who participated in clinical studies and methodological approaches for study analyses to assess the critical variables influencing an association between MHT and risk of neurodegenerative diseases. Outcomes of the review indicated that: (1) observational studies assessed outcomes of MHT in symptomatic women whereas MHT clinical trials were conducted in asymptomatic postmenopausal women not treated for menopausal symptoms, (2) in asymptomatic postmenopausal women, late MHT intervention was of no benefit, (3) different MHT treatments and regimens between observational studies and clinical trials may impact outcomes, and (4) observational studies may provide greater predictive validity for long-term neurological health outcomes as MHT was introduced in symptomatic women and administered over a long period of time. Going forward, achieving precision hormone therapy will require a priori identification of symptomatic women appropriate for MHT and the type and dose of MHT appropriate for their genetic profile and health risks.

Chinese abstract

自从20世纪40年代开始绝经激素治疗(MHT)以来, 人们进行了随机临床试验和观察性研究, 以确定MHT的获益与风险。然而, MHT的疗效仍然存在争议, 因为包括基因标志物和病史在内的多种因素导致了神经退行性疾病的个体间差异。在此, 我们回顾了参与临床研究的女性的特征和研究分析的方法学, 以评估影响MHT和神经退行性疾病之间风险关联的关键变量。综述结果显示：（1）观察性研究是在有症状的妇女中评估MHT的结局, 而MHT临床试验是在不治疗更年期症状的无症状妇女中进行的；（2）在无症状的绝经后妇女中, 晚期MHT干预无益；（3）观察性研究和临床试验中不同的MHT治疗和方案可能影响结局；（4）因为MHT在有症状的妇女中应用并长期应用, 观察性研究可能为远期神经健康结局提供更高的预测效度。未来, 实现精准激素治疗需要预先鉴别出适合MHT的有症状女性以及适合其遗传和健康风险的MHT类型和剂量。

Keywords:

• Precision medicine
• menopausal hormone therapy
• Alzheimer’s disease
• cognitive decline
• menopause
• estrogen
• progesterone

Potential conflict of interest

The authors report no conflict of interest.

Additional information

Funding

This work was supported by the NIH [grant R37AG053589], [grant 1R01AG057931], [grant P01-AG026572] to R.D.B. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.