Friday, January 1, 2016

Estrogen Replacement in Anorexia Nervosa

Young females with anorexia nervosa (AN) suffer many adaptive, physiological changes, including endocrine changes such as low estrogen levels, low levels of insulin-like growth factor 1 (IGF-1), higher levels of cortisol and alterations in other hormones. These hormonal changes can have deleterious effects on bone development and peak bone mass—the maximum amount of bone an individual will have during her/his lifetime—putting girls at increased risk for bone deficits later in life.

Although estrogen deficiency is a significant contributor to low bone density in adolescents with AN, studies have shown that oral doses of estrogen are ineffective in increasing bone density in this population.

A team at MassGeneral Hospital for Children and Massachusetts General Hospital, led by Madhusmita Misra, MD, chief of the Division of Pediatric Endocrinology, and Anne Klibanski, MD, chief of the Neuroendocrine Unit, explored this estrogen deficiency and strategies for estrogen replacement in AN. Oral delivery of estrogen may have reduced efficacy because it undergoes hepatic first-pass metabolism, which leads to a decrease in IGF-1, a hormone that contributes greatly to bone formation during puberty. Levels of IGF-1 are already low in patients with AN, and oral estrogen may be a further suppressive factor.

The team studied the transdermal delivery of estrogen for AN patients, a method that bypasses first-pass metabolism in the liver (1). They also looked at dosages tailored to maturity, based on previous studies suggesting that very low doses of oral estrogen, which mimic the small rises in estrogen during early puberty, showed less inhibition of IGF-1.

The study randomized girls with AN ages 12–18 to either estrogen or placebo and followed them for an 18-month period. They grouped the girls according to bone age: If their bones were still growing, they were given very small, incremental doses of oral estrogen to mimic the early increases in estrogen during puberty. Girls who had completed bone growth received the transdermal estrogen patch at a full replacement dose to match what their bodies would normally produce, with cyclic progesterone.

Differences in bone density changes between AN girls receiving placebo (purple), AN girls receiving physiologic estrogen replacement (blue), and normal-weight controls with AN (orange). The AN girls receiving physiologic estrogen replacement showed an increase in bone density similar to that of normal-weight girls without AN, while the girls with AN who receiving a placebo showed a decrease in bone density over the 18-month study (*p<0.05).

Girls who received physiologic estrogen replacement, whether low-dose oral or transdermal, had a significant increase in bone density, which approximated levels seen in normal-weight controls without AN. There were no significant side effects and no difference in weight gain between girls who received physiologic estrogen in either form and girls given placebos.

Physiologic estrogen replacement led to a significant decrease in anxiety trait (but not state) scores, as measured by the State-Trait Anxiety Inventory for Children (STAIC). AN-E+ represents girls with AN who received estrogen. AN-E- represents girls with AN who received a placebo (*p<0.05).

The team also found that participants who received the transdermal patch showed significant improvements in anxiety scores over the study duration—in particular, trait anxiety decreased (2). Rodent studies had previously shown that estrogen is protective against anxiety. Additionally, girls with AN who did not receive estrogen and who gained weight over the follow-up period showed an increase in state anxiety and body dissatisfaction, which is a core consideration in treatment. In contrast, girls who received estrogen and gained weight did not show this increase in state anxiety or body dissatisfaction, suggesting that physiologic estrogen replacement might not only help bone density but assist the psychological process of recovery from AN as well.


(1) Misra M, D Katzman, K Miller et al. “Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa.” Journal of Bone and Mineral Research 26, no. 10 (October 2011): 2430–38.

(2) Misra M, D Katzman, N Estella et al. “Impact of physiologic estrogen replacement on anxiety symptoms, body shape perception, and eating attitudes in adolescent girls with anorexia nervosa: data from a randomized controlled trial.” Journal of Clinical Psychiatry 74, no. 8 (August 2013): e675–e771.

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