Transdermal Estrogen in Older Premenopausal Women with Anorexia Nervosa

 描述（由申请人提供）：神经性厌食症（AN）影响美国0.5-1%的大学年龄女性，其特征是极端的自我诱导饥饿。在与AN相关的许多医学共病中，严重的骨丢失是最常见的，并且尽管体重恢复，但通常仍持续存在。重要的是，这种骨质流失与骨折风险增加有关;一项前瞻性研究表明，与年龄匹配的对照组相比，AN女性的骨折风险增加了7倍。因此，预防与AN相关的严重骨丢失的治疗至关重要，但目前还没有批准用于AN相关骨丢失的治疗方法。闭经和由此导致的低雌激素血症是AN女性的特征性表现，是这种疾病中骨量丢失的重要因素。这一点得到了以下事实的支持，即闭经的持续时间与AN女性的骨密度（BMD）呈负相关。然而，尽管存在这种关联，调查口服雌激素对AN女性影响的初步研究并未显示出益处。这可能是由于口服雌激素抑制了IGF-I的产生-这是骨形成的重要介质。重要的是，IGF-I是一种营养介导的激素，在AN女性中的水平已经很低，这些低水平是低骨量的重要因素。因此，口服雌激素进一步抑制IGF-I可加重骨量丢失。与口服雌激素不同，经皮雌激素不具有相同的IGF-I抑制作用，并且在健康的绝经后妇女中，经皮雌激素增加IGF-I水平。经皮雌激素可增加AN少女的BMD，但由于AN女性的骨转换与青少年有很大不同，经皮雌激素是否会改善年龄较大的绝经前AN女性的BMD目前尚不清楚。Fazeli博士是哈佛医学院的医学助理教授和马萨诸塞州总医院（MGH）的医学助理。她是在MGH神经内分泌单位的工作人员，并致力于她的大部分时间用于临床研究。她得到了MGH的大力支持，并可以充分利用神经内分泌科、临床研究中心和哈佛Catalyst CTSC的资源。她的共同导师安妮·克里班斯基博士和玛丽·布克森博士资金充足，并对法泽利博士的研究方向进行了投资。在K23获奖期间，Fazeli博士已经在哈佛公共卫生学院获得了生物统计学和研究设计方面的关键培训，并获得了公共卫生硕士学位。她还发表了一篇第一作者论文，证明了特立哌酮对AN女性BMD的影响（她的K23奖的特定目标1）。如果获得，这笔赠款将支持Fazeli博士获得R 01应用调查的关键初步数据。 特立哌酮和经皮雌激素替代治疗对老年绝经前AN妇女骨密度的影响。

 DESCRIPTION (provided by applicant): Anorexia Nervosa (AN) affects 0.5-1% of college-aged women in the US and is characterized by extreme, self- induced starvation. Of the many medical co-morbidities associated with AN, severe bone loss is the most common and often persists despite weight recovery. Importantly, this bone loss is associated with an increased risk of fracture; a prospective study demonstrated that women with AN have a 7-fold increased risk of fracture compared to age-matched controls. Therefore, a treatment to prevent the severe bone loss associated with AN is critical, but there are currently no approved treatments for AN-associated bone loss. Amenorrhea and resultant hypoestrogenemia, which are characteristic findings in women with AN, are significant contributors to the loss of bone mass in this disease. This is supported by the fact that duration of amenorrhea is inversely associated with bone mineral density (BMD) in women with AN. Yet, despite this association, initial studies investigating the effects of oral estrogen in women with AN did not demonstrate a benefit. This is likely due to the fact that oral estrogen suppresses production of IGF-I - an important mediator of bone formation. Importantly, IGF-I is a nutritionally-mediated hormone and levels are already low in women with AN and these low levels are an important contributing factor to the low bone mass. Therefore further suppression of IGF-I by oral estrogen can exacerbate the loss of bone mass. Unlike oral estrogen, transdermal estrogen does not have the same IGF-I-suppressing effects and in healthy, postmenopausal women transdermal estrogen increases IGF-I levels. Transdermal estrogen increases BMD in adolescent girls with AN but because bone turnover is quite different in women with AN compared to adolescents, whether transdermal estrogen will improve BMD in older, premenopausal women with AN is currently unknown. Dr. Fazeli is an Assistant Professor of Medicine at Harvard Medical School and Assistant in Medicine at Massachusetts General Hospital (MGH). She is on staff in the Neuroendocrine Unit at MGH and devotes the majority of her time to clinical research. She is well-supported by MGH and has full access to the Neuroendocrine Unit, Clinical Research Center and Harvard Catalyst CTSC resources. Her co-mentors, Drs. Anne Klibanski and Mary Bouxsein, are well-funded and invested in the direction of Dr. Fazeli's research. During the course of her K23 award, Dr. Fazeli has already obtained critical training in biostatistics and research design at the Harvard School of Public Health, from which she earned a Master of Public Health degree. She has also published a first-author paper demonstrating the effects of teriparatide on BMD in women with AN (Specific Aim 1 of her K23 award). If awarded, this grant will support Dr. Fazeli in obtaining critical preliminary data for an R01 application investigating the effects of teriparatide and transdermal estrogen replacement on bone mineral density in older, premenopausal women with AN.