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. Androgens 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 therapyinduced 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.
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PUBLICATIONS
- Dimitrakakis C, Bondy CA. The role of androgens in mammary gland growth
and neoplasia. In: Pundali A, ed. Recent research developments in endocrinology.
- Dimitrakakis
C, Zhou J, Bondy CA. Androgens, mammary growth and neoplasia. Fertil
Steril, in press.
- Ross
JL, Roeltgen D, Feuillan P, Kushner H, Cutler GB Jr. Use of estrogen
in young girls with Turner syndrome: effects on memory. Neurology 2000;54:164-170.
- Ross
JL, Roeltgen D, Kushner H, Wei F, Zinn AR. The Turner syndrome-associated
neurocognitive phenotype maps to distal Xp. Am J Hum Genet 2000;67:672-681.
- Ross
JL, Stefanatos G , Kushner H, Zinn A, Bondy C, Roeltgen D. Persistent
cognitive deficits in adult women with Turner syndrome. Neurology, in
press.
- Ross
J, Zinn A, McCauley E. Neurodevelopmental and psychosocial aspects
of Turner syndrome. Ment Retard Dev Disabil Res Rev 2000;6:135-141.
- Zhou J, Ng S, Vendola K, Bievre M, Bondy CA. Testosterone inhibits
estrogen-induced mammary epithelial proliferation. FASEB J 2000;14:1725.
- Zinn
AR, Ross JL. Molecular analysis of genes on Xp controlling Turner
syndrome and premature ovarian failure (POF). Semin Reprod Med 2001;19:141-146.
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