Scientist explain a drug's paradoxical action: discovery may lead to new therapies for breast cancer, early puberty

What could be the explanation for a drug that works at low doses to help children with one type of early puberty - but requires doses ten times higher to treat a similar disease? For years, this puzzle has intrigued pediatric endocrinologists, the doctors who care for children with abnormal hormone systems.

Now scientists at UC San Francisco, working with a new experimental model that turns yeast cells into little versions of human adrenal glands, have learned the answer: they have shown how the drug, medroxyprogesterone acetate (MPA) inhibits one of the key enzymes necessary to produce steroid hormones.

MPA more commonly is known by its brand name, Provera. Often prescribed as a hormone replacement therapy during menopause, it sometimes is used to treat small children who develop breasts, enlarged testicles and other sex characteristics. In high doses it is used to treat women with breast cancer.

The research, published in the June issue of The Journal of Clinical Endocrinology and Metabolism, was conducted by second year Tufts University medical student Tim Lee and UCSF research scientist Richard Auchus, MD, PhD, in the laboratory of Walter L. Miller, MD, UCSF professor of pediatric endocrinology. The study, conducted on a summer research grant from the Society for Pediatric Research (SPR), earned Lee a prestigious Medical Student Research Award at the annual meeting of the Society for Pediatric Research in May. Lee and Auchus were looking for a way to explain MPA's dual mechanism of action. Normally, puberty starts in the pre-teen years, when certain cells in the brain begin pulsing out small timed doses of a chemical signal called GnRH, for gonadotropin releasing hormone. GnRH instructs the ovaries and testes to start making steroids, including sex hormones. For children who start to develop sex characteristics very early - as young as toddler age - Provera is one of a number of drugs that can be used to delay the onset of puberty. Scientists al

Contact: Janet Basu
University of California - San Francisco

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