Estrogen treatment for tall stature in adolescent girls : short-and long-term effects on the breast

Adolescent tall girls have been treated with high-dose estrogens to reduce their final height for psychosocial reasons since the 1950s. Although the practice is uncommon now, a recent. survey of US paediatric endocrinologists reported that 96 (23%) of 411 respondents had treated girls in the 'preceding 5 years. Exposure to high-dose estrogen during the pubertal mammary development stage could have long-term effects on breast histology, function and disease. This study investigated the breast related side effects of treatment in a retrospective cohort study of Australian girls who, between 1953 and 1993, were assessed for tall stature in adolescence and either treated with high-dose estrogens (diethylstilbestrol or ethinyl estradiol) or untreated. Breast related side effects experienced during treatment; subsequent effects on lactation (breastfeeding initiation and duration), breast disease or investigations (e.g. breast biopsies); and mammographic density, a well established risk factor for breast cancer, were examined over two follow-up periods. At the first follow-up (2002-2003) demographic information, details of assessment and treatment, and short-term side effects of treatment were collected from 371 treated and 409 untreated women via postal questionnaire. History of breast disease and investigations, pregnancy and breastfeeding history were collected by computer assisted telephone interview (CATI). Treatment and anthropometric variables in adolescence were obtained from medical records where available. At the second follow-up (2006-2007), 167 treated and 142 untreated women aged 40 years or older provided access to a recent mammogram from which dense area, percent density, non-dense area and total breast area were measured using a computer assisted thresholding method. Additional risk factor data were collected and/or updated in a second CATI. Short-term effects of treatment reported by the women included breast lumps, galactorrhea, breast pain, dry cracked or bleeding nipples and increased pigmentation of the nipple and areolae. These effects were more frequently reported in women treated with diethylstilbestrol. Compared to untreated women, treated women were no more likely to have ever had a breast biopsy, breast surgery, or a diagnosis of breast cancer. There was no significant difference in the average duration of breastfeeding between treated and untreated women, and treated women were no more likely to not commence breastfeeding. Mammographic findings showed that treated women had a significantly lower mean dense area than untreated women but did not differ significantly in mean percent density, non-dense area or total breast area. The short-term side effects of treatment reported by women in this study would have caused discomfort and possibly embarrassment in adolescence. However, this investigation provides some reassurance for women treated with high-dose estrogens for tall stature that treatment 'does not appear to affect their ability to lactate or increase their risk of having breast disease requiring a breast biopsy or surgery, and is unlikely to increase their risk of breast cancer through mechanisms related to mammographic density. The study also has broad implications for our understanding of the biology of breast development and for breast cancer research. It has shown us that exposure to sex hormones during adolescence can have a sustained effect on breast tissue as demonstrated by a reduction in mammographic dense tissue in adulthood.