All 6 billion people alive today owe their lives to a hormone calledprogesterone. As its name implies, this pro-gestation compound setsin motion the cascade of events that releases a human ovum from itsovary, preps the lining of the uterus to give the egg a nest, andeventually sends the resulting fetus on its way to the outside worldvia the progesterone-conditioned vaginal birth canal. After that, thehormone stimulates milk production.

The same progesterone blocks further ovulation, once an egg hasbeen fertilized. This accounts for its prime role in oral contraception.

In males, that steroid hormone is thought to promote sperm motility.

Besides its best-known source in the female gonads, progesterone isalso manufactured by the cortex of the adrenal glands _ whence theterm corticosteroid.

Over a decade ago, a French neuroendocrinologist, Etienne Baulieu,discovered that a sizable fraction of the brain's glial cells also secreteprogesterone. At the time, Baulieu coined the term "neurosteroid," todenote this cerebral source of endocrine hormones.

"We were very surprised," Baulieu told BioWorld Today, "to findthat besides genital and adrenal glands, the nervous system formedsteroids too. So the next question we asked was: `Do they doanything there?' "

He explained: "Steroids are known as compounds that modify geneexpression, therefore protein synthesis, and thus shape the growthand life span of cells. So we looked for a system where we could tryto demonstrate such an effect."

Among the brain's glial cells (which outnumber its neurons 10-to-one), some glia, the oligodendrocytes, perform the chore of wrappingneuronal axons in myelin. This myelin sheath, for all the world likethe rubber and woven textile layers of insulation around an electriccable, speeds the transmission of nerve messages along the axonalfibers.

Myelin surrounds the axons in many concentric lamellae of lipid -mainly cholesterol - separated by thinner layers of protein. When anerve regenerates after an injury, oligodendrocytes in the brain, glialSchwann cells in peripheral nerves, remyelinate the newly restoredaxons.

What Myelin Protects Demyelination Puts Asunder

Multiple sclerosis is the prime example of a disease in which themyelin sheath somehow self-destructs. Gradually, over many years, itstrips sections of the axonal fibers bare, interrupting or scramblingtransmission of nerve impulses, particularly those serving vision,sensation and use of the limbs.

"Not knowing which cells were making the progesterone in thebrain," Baulieu continued, "we bet on oligodendrocytes as a possiblesource. We found that indeed these myelinating glial cells weremaking steroids. But then," said Baulieu, who chairs the laboratory ofbasic research into human reproduction at the College de France inParis, "I decided that the brain was too complex for us. Instead, weturned to a simpler system, the peripheral sciatic nerve."

His colleagues measured steroids in the sciatic nerves of humancadavers, "and we found a lot." Baulieu reported these and ensuingexperiments in the current issue of Science, dated June 9, under thetitle: "Progesterone synthesis and myelin formation by Schwanncells."

Schwann cells are the glia that myelinate peripheral nerve cells,analogous to the oligodendrocytes, which do as much for the centralnervous system (CNS).

To measure the role of progesterone in myelin repair of damagedaxons, Baulieu reported in Science, "we inhibited its synthesis oraction . . . by RU-486 [the current leading abortifacient drugcandidate] a potent competitive antagonist of progesterone at thereceptor level." It decreased the thickness of myelin sheaths.Conversely, progesterone applied close to the sciatic repair site"significantly increased the myelin sheath thickness, suggesting thatremyelination may be enhanced by high doses of neurosteroids."

Trembler mice simulate the demyelination occurring in multiplesclerosis patients. The French researchers found low concentrationsof progesterone, and of its precursor molecule, pregnenolone, in thesciatic nerves of this animal model. Pregnenolone's precursor ischolesterol, the main ingredient of myelin. Baulieu pointed out thatpregnenolone "can be synthesized from . . . cholesterol by Schwanncells in culture."

Baulieu said in an interview, "we found gene expression of specificproteins, and evidence of synthesis of progesterone action, especiallyin Schwann cells." He plans to present those data to the 25th annualmeeting of the Society for Neuroscience next November in SanDiego.

Meanwhile, he said, "we hope to design the most crucial types ofexperiments, in animal models which more or less reproduce thehuman diseases of demyelination, such as multiple sclerosis."

Baulieu described "a very new technique, taking nerves duringsurgery and culturing human cells." So far, his group is studying"whether human Schwann cells have the same sort of progesteronesynthesis and effect that we find in mice and rabbits."

He said, "I wouldn't be surprised if there is really a clear cutseparation between the general system of progesterone, the sexhormone, and local progesterone, [such as Schwann cells make],which has nothing to do with sex."

He and his co-authors "have started experiments of that sort inanimals, injecting them with a lot of progesterone to see if it willchange their myelination, and so on."

Someone's Got To Do It

Asked about the prospects of eventual human therapeutic trials formultiple sclerosis, Baulieu replied, "I would love to do that, but I'mnot sure I have the technical possibility.

"But I'm sure," he surmised, "that some people will do that if wedon't."

Stanford University Neurobiologist Barbara Barres is also sure "thatmany people, when they read Baulieu's findings, may decide to starttheir own clinical trials, for example comparing the efficacy ofprogesterone for treating multiple sclerosis with on-going trials ofbeta-interferon. (See BioWorld Today, May 16, 1995, p. 1.)

Barres' own research has established that steroids in the centralnervous systems constantly signal adjacent nerve cells not to commitapoptosis. "They are really trying to kill themselves," she toldBioWorld Today, "unless their neighboring cell says, `Don't do it!Don't do it!' "

In characterizing those survival signals for oligogliocytes, sheobserved, "it turned out that progesterone was one of them." Barresdeems Baulieu's latest finding "pretty cool; pretty interesting; anotherimportant step forward, in showing a clear potential function forthose neurosteroids, which is to promote myelination." n

She concluded: "Between his results in the peripheral nervous systemand ours in the central nervous system, this might help promoteremyelination in multiple sclerosis patients.

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.

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