The Unit on Turner Syndrome conducts clinical studies comparing the effects of GH with and without gonadal steroids on longitudinal growth and cognitive function in girls with the disorder. The results of long-term, double-blinded studies will be available within a few years. We have recently initiated genotype-phenotype studies aimed at elucidating X-chromosome genes responsible for abnormalities in the development and function of the brain, cardiovascular system, and ovary in Turner syndrome. The new studies are also focusing on the clinical characterization and genetic tracking of the metabolic disorders, including osteoporosis, glucose intolerance, hypertension, and dyslipidemia, which affect 30 to 40 percent of adults with Turner syndrome.

Turner Syndrome Studies
Zhou, Dimitrakakis, Bondy
The unit is also investigating two different hormone replacement regimens in older girls and women with Turner syndrome. A randomized, double-blind study compares the effect of estrogen with that of estrogen plus testosterone in preventing osteoporosis, promoting normal body composition, and affecting aspects of mood and behavior. In addition, we will evaluate the hypothesis that testosterone limits estrogen-induced breast stimulation. Androgens are normally abundant in healthy women and actually are relatively more abundant than estrogens throughout the entire life cycle. On a daily basis, the normal ovary produces substantially more total testosterone than estradiol. Thus, girls and women with Turner syndrome with absent ovarian function exhibit reduced androgen as well as estrogen production. The beneficial effects of replacing ovarian estrogen in women with ovarian failure therapy are well recognized, but the potential benefits of replenishing missing ovarian androgens have not been addressed. Androgen’s normal physiological role in women is thought to involve augmentation of lean body mass, energy, and libido. We have proposed that another important role for endogenous androgen in women is to protect the mammary gland from “unopposed” estrogenic stimulation.

The Role of Ovarian Androgens
To investigate the role of endogenous androgen in regulating mammary epithelial proliferation, we treated normally cycling rhesus monkeys with flutamide, an androgen receptor antagonist. Mammary epithelial proliferation (MEP) was increased by about 50 percent in the flutamide-treated group, indicating that androgen receptor activation normally suppresses MEP. To evaluate the efficacy of physiologic androgen supplementation in limiting estrogen replacement therapy–induced MEP, we employed an ovariectomized rhesus monkey model of menopause. MEP was increased about four-fold in the estradiol and estradiol plus progesterone treated groups but was not different from vehicle-treated control in the estradiol plus testosterone group. The observations suggest that endogenous androgens normally limit MEP and that androgen supplementation of estrogen therapy may reduce estrogen-induced MEP and breast cancer risk.