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Hormone Therapy in Rehab

 A COMPOUND SCREEN:Screening strategy used to (A) identify mechanistically distinct antiprogestins and (B) to identify estrogen receptor (ER)-sparing antiprogestins.Click for larger version of diagram (33K) Progestins, synthetic progesterone analogs, joined estrogen as part of hormone replacement therapy (HRT) some two decades ago, to reduce perceived risks of endometrial cancer from estrogen alone. But for almost as long, researchers have suspected that progestins block some benign effec

By | November 17, 2003

 A COMPOUND SCREEN:
Screening strategy used to (A) identify mechanistically distinct antiprogestins and (B) to identify estrogen receptor (ER)-sparing antiprogestins.
Click for larger version of diagram (33K)

Progestins, synthetic progesterone analogs, joined estrogen as part of hormone replacement therapy (HRT) some two decades ago, to reduce perceived risks of endometrial cancer from estrogen alone. But for almost as long, researchers have suspected that progestins block some benign effects of estrogen replacement, increasing the risk of breast cancer, diminishing estrogen's beneficial effects on the cardiovascular system, and souring mood. So, researchers continue to study progestins in search of safer HRT.

Jon Nilsen and Roberta Brinton, University of Southern California, recently showed how natural estrogen and progesterone protect hippocampal neurons from glutamate toxicity. But at least one progestin, medroxyprogesterone acetate (MPA), blocks that protection.1 MPA is the progestin component of Prempro, the HRT used in the Women's Health Initiative (WHI) clinical trials. The US government shut down that arm of the WHI study in July 2002--three years early--after discovering small increases in breast cancer, heart disease, stroke, and pulmonary embolism in women taking the drug.

A MARKETING NIGHTMARE No one argues that MPA is solely responsible for those risk increases, but many argue that the results would have been different for progesterone or different progestins.2 Researchers are not unanimous on MPA, but even its backers concede that the future is gloomy. "The whole idea that progestin is bad and has been responsible for some of the negative findings of the WHI, I really think, is an overextrapolation," says Duke University's Donald McDonnell. He acknowledges candidly, however, that MPA partisans can't overcome its increasingly bad reputation. "There has to be a shift toward a newer progestin purely to address that marketing need," McDonnell says.

Investigators are tackling that need in several ways. McDonnell and his colleagues are looking for new antiprogestins that will act as selective progesterone receptor modulators (SPRMs), uncovering progesterone receptor pharmacology in the same way that selective estrogen receptor modulators (SERMs) have helped illuminate estrogen receptor action. Existing antiprogestins are promiscuous; while it's not quite true that they will snuggle up to any passing receptors, they embrace a great many. RU486, the standard antiprogestin, interacts with receptors for mineralocorticoids, glucocorticoids, androgens, and even ERß, an estrogen receptor.

The Duke researchers have identified two new groups of antiprogestins.3 One acts like pure antiprogestins; its members cleave to the progesterone receptor alone, changing its shape in a way that prevents binding by two coactivators. The second class of compounds retains some crucial RU486-like activity yet ignores ERß.

Brinton reports that she and her colleagues also are hunting for SPRMs. "Our ultimate goal is to develop molecules that will selectively activate progestin and estrogen actions in brain, to develop what we call a neuroSERM and a neuroSPRM," she says. That will involve determining whether the hormone receptors in brain are exactly like those elsewhere. Specific receptor splice variants, she says, may activate the cell-signaling cascades crucial for neuroprotection and memory. "If you have a receptor that is unique to a particular organ or a particular set of cells within that organ, it's then possible to design molecules that selectively activate that receptor versus others," she says.

CLOSER TO PHYSIOLOGY In addition to looking for new molecules, some researchers, including Brinton, focus on existing progestins, some of which turn out to be more attractive than MPA. Regine Sitruk-Ware of the Population Council in New York City reports that she and her colleagues are working on Nestorone, a progestin shelved by Merck & Co., Germany, because it has a non-oral mode of action. Nestorone interacts only with the progesterone receptor and is extremely active at very low doses when absorbed through the skin in patches or gels. Although the Population Council is interested chiefly in Nestorone's potential as a contraceptive, the progestin has great potential for use in HRT. "We have some preliminary data showing that a low dose of 1 mg in gel can be sufficient to transform the endometrium and protect the endometrium from hyperplasia," she says.

Perhaps some day, says McDonnell, endometrium protection will no longer be necessary, and progestins can be discarded from HRT. "If we could develop a compound--and I think it can be done--that can selectively inhibit estrogen action in the uterus with modest effects in other tissues, then I think that drug will definitely be received well."

Tabitha M. Powledge (tam@nasw.org) is a freelance writer in the greater Washington, DC, area.

References
1. J. Nilsen, R.D. Brinton, "Divergent impact of progesterone and medroxyprogesterone acetate (Provera) on nuclear mitogen-activated protein kinase signaling," Proc Natl Acad Sci, 100:10506-11, Sept. 2, 2003.

2. T.M. Powledge, "Hormone researcher revolt," The Scientist, Aug. 22, 2003, available online at www.the-scientist.com/news/20030822/01

3. G. Sathya et al., "Identification and characterization of novel estrogen receptor-beta-sparing antiprogestins," Endocrinology, 143:3071-82, 2002.

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