Rosenﬁeld et al 2005; Soriano et al 2005; Bondy et al 2006). Replacement therapy is usually begun with one-tenth of the adult replacement dose. The initial dose (oral ethinlyestra- diol: 2 μg/day) is then gradually increased over 2 to 3 years in order to fully mimic physiologic increases of estradiol during normal puberty so that normal breast and uterine develop- ment may occur. The adult replacement doses which achieve estradiol levels in the normal range for young adult women are: oral ethinylestradiol: 20 μg/day, transdermal estradiol: 0.1 mg/day or injectable estradiol cypionate: 2.5 mg/month (Bondy et al 2006). The addition of progestin is recom- mended at least 2 years after starting estradiol or when breakthrough bleeding occurs. It is also imperative to teach the TS patient that estrogen therapy is usually required until the time of normal menopause (52–54 years of age) in order to maintain normal feminization and prevent osteoporosis in the future (Hogler et al 2004). Bone mineral density The effect of recombinant hGH therapy on bone mineral density (BMD) and body composition has also been studied in TS girls and it was found that GH treatment alone, without the combination with estradiol, had little effect on cortical or trabecular BMD although it did increase lean body mass and it reduced adiposity (Ari et al 2006). Also, whole body and lumbar spine BMD in adult TS patients who received only hGH therapy without hormone replacement therapy (HRT) with estradiol until the age of 17 showed decreased BMD which was not improved with HRT during adulthood since normal peak bone mass in these patients was never attained because of the delay in HRT (Suganuma et al 2003). This study emphasizes the importance of the initiation of estradiol therapy at a normal age of puberty in order to maximize peak bone mass at an appropriate age in order to avoid osteoporosis during adulthood. Safety of therapy The safety of hGH therapy in girls with TS has been an issue of much discussion. The effects of hGH on glucose metabolism has been addressed in many studies and although insulin levels increase signiﬁcantly during hGH therapy in TS, compared to baseline, no glucose intolerance was uncov- ered and the insulin levels return to normal levels after the completion of the hGH therapy (Wilson et al 1991; Welse et al 1993; Sas et al 1999a; Van Teunenbrock et al 1999; Bannink et al 2006a). The impact of recombinant hGH therapy on the cardiovascular system has also been studied because many girls with TS have anatomic malformations Therapeutics and Clinical Risk Management 2008:4(6) GH and Turner syndrome affecting the heart, aorta and other major vessels, together with hypertension and abnormalities of heart rate, cardiac conduction and repolarization. Seven years of hGH treat- ment in TS girls was shown to have no adverse effects on left ventricular heart dimensions or blood pressure (Wilson et al 1991). Echocardiographical studies showed normal left ven- tricular morphology and function in GH-treated TS girls and magnetic resonance angiography found no deleterious effects of hGH treatment on aortic diameter or compliance (Sas et al 1999b; Radetti et al 2001; Bondy 2006; Vab deb et al 2006; Bondy 2007). Also no increased risk of neoplasia has been found in TS girls treated with hGH (Bondy 2007). In conclusion, recombinant human GH therapy in com- bination with estradiol starting at the normal age of puberty is the treatment of choice for the treatment of short stature in girls with TS. Growth hormone therapy seems to be safe, with no adverse effects so far, on glucose metabolism or car- diac function or any association with neoplasms, but further studies are needed to give conclusive data on the issue of long-term safety. Nevertheless, most studies report that GH and estradiol therapy allows the girls with Turners Syndrome to attain normal adult height, pubertal development and bone mass and to maintain a good quality of life. Disclosures The author has no conﬂicts of interest to disclose. References Ankarberg-Lindgren D, Elfving M, Wikland KA, et al. 2001. Nocturnal application of transdermal estradiol patches produces levels of estradiol that mimic those seen at the onset of spontaneous puberty in girls. J Clin Endocrinol Metab, 86:3039–44. Ari M, Bakalov VK, Hill S, Brody CA. 2006. The effects of growth hormone treatment and bone mineral density and body composition in girls with Turner syndrome. J Clin Endocrinol Metab, 91:4302–5. Bannink EM, van Doorn J, Stijnen T, et al. 2006a. Free dissociable insulin- like growth factor I (IGF-I), total IGF-I and their binding proteins in girls with Turner syndrome during long-term growth hormone treat- ment. Clin Endocrinol (Oxf ),65:310–9. Bannink EM, Raat H, Mulder PG, et al. 2006b. Quality of life after growth hormone therapy and induced puberty in women with Turner syndrome. J Pediatr, 148:95–101. Binder G, Ranke MB, Martin DD. 2003. Auxology is a valuable instrument for the clinical diagnosis of SHOX haploinsufﬁciency in school-age children with unexplained short stature. J Clin Endocrinol Metab, 881:4891–6. Binder G, Baur F, Schweizer R, et al. 2006. The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children. J Clin Endocrinol Metab, 91:659–64. Blaschke RJ, Rappold G. 2006. The pseudoautosomal regions, SHOX and disease. Curr Opin Genet Dev, 16:233–9. Blum, WF, Crowe BJ, Quigley CA, et al. 2007. Growth hormone is effective in treatment of short stature associated with short stature homeobox- containing gene deﬁciency: two-year results of a randomized, controlled multicenter trial. J Clin Endocrinol Metab, 92:219–28. 1181