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Discoveries Hold Promise for Dysfunctional Labor.

BIG SKY, MONT.-Recent discoveries in genetics and molecular biology may soon give obstetricians new, highly targeted tools for management of dysfunctional labor, Dr. Mark Phillippe reported at an ob.gyn. update sponsored by the University of Chicago.

Gene coding for many of the key parturitional hormones and hormone receptors have been identified, and the complex chemical interactions that regulate parturition are far better understood than they were a decade ago.

Delayed or premature parturition, especially if it happens repeatedly in the same patient, may reflect genetic anomalies, proposed Dr. Phillippe, professor of maternal-fetal medicine at the university

"As our understanding of the biology of myometrial contractions continues to advance, there will be a lot of targets for inducing appropriately functional labor," he said in an interview.

"Right now we are identifying the [molecular] players that contribute to dysfunctional labor. But in the next 5 or 10 years, we may be able to identify specific genetic or molecular abnormalities that can be targeted for therapy," Dr. Phillippe predicted.

Better knowledge of the genetic and endocrine factors regulating parturition could profoundly affect patient management decisions, particularly as they relate to vaginal birth after cesarian section (VBAC).

"A failed VBAC is worse than no VBAC at all," said Dr. Phillippe. "If you can identify a particular genetic or functional abnormality that contributes to repeatedly dysfunctional labor, you could avoid attempting VBACs in patients for whom it is almost guaranteed not to work."

So far, only one gene-linked anomaly related to abnormal labor has been discovered: placental sulfatase deficiency. This X-linked recessive disorder is extremely rare, occurring in only 1 in 2,000-6,000 pregnancies. It is commonly associated with congenital ichthyosis.

In women with this abnormality, the placenta is unable to convert androgen sulfates into estrogens, resulting in low serum estriol concentrations. The ultimate result is poor cervical dilation, faltering myometrial contractions, and ultimately prolonged pregnancy

While no other distinct genetic defects have yet been found, Dr. Phillippe believes there are likely to be many more. And researchers are increasingly confident about where to look for them.

In the last decade, gene coding for a host of gestational and parturitional hormones, receptors, and enzymes have been identified and cloned, including oxytocin (chromosome 20p13); oxytocin receptor (3p26); human chorionic gonadotropin (19q13.3); prolactin (6p21); and human placental lactogen (17q22-24). Researchers also have identified gene loci coding for estrogens, progesterones, and their various receptors.

Dr. Phillippe said considerable research is now underway to investigate the role of possible oxytocin deficiencies in delayed parturition. "We know many women falter during labor, and this may be a reflection of mutations in the genes for oxytocin or its receptor.

Oxytocin release from the pituitary as well as the placenta increases markedly in the early phases of labor, as does production of oxytocin receptor proteins by the myometrium and the myoepithelial cells of the breast. These processes are, in turn, driven by estrogens. Binding of oxytocin to its receptors triggers massive influx of calcium into the myometrial cells, resulting in phasic myometrial contractions.

While oxytocin is clearly an important player in the evolution of parturition, experiments with knock-out mice lacking the gene for this hormone indicate that normal labor can emerge even in the absence of oxytocin. It is, Dr. Phillippe said, "sufficient for the onset of parturition but not necessary."

Human placental lactogen (HPL), which is synthesized by the syncytial trophoblasts and reaches peak production at the 40th gestational week, is another key hormone of pregnancy. It plays a critical role in regulating both maternal and fetal glucose metabolism.

HPL shows significant homology with both human growth hormone and prolactin.

The enzyme 5-[alpha]-reductase, which is responsible for conversion of testosterone to dihydrotestosterone, is another key player in the timing of labor and delivery. Studies of knock-out female mice lacking the gene for type 1 5-[alpha]-reductase show that more than two-thirds had prolonged gestation, by as much as 2 days.

"The human equivalent of 2 mouse days is going to 44 weeks," Dr. Philippe said.

While 5-[alpha]-reductase gene anomalies have yet to be found in humans with delayed parturition, it is an increasingly important focus of study.

Estrogens are produced in "industrial-strength concentrations" ever the course of gestation and have multiple regulatory effects on the parturitional process. With three types of estrogens (estradiol, estriol, and estrone) and 30 different types of steroid hormone receptors found in a diverse range of tissues, the role of estrogen in regulating labor is almost a field unto itself.

Levels of all three estrogens rise steadily over the course of gestation and peak during parturition. But estriol, which is far weaker than estradiol in terms of its receptor-binding potency shows the most precipitous climb, soaring from almost unmeasurable levels before pregnancy to levels that exceed estradiol.

This fact begs a major question regarding the specific parturitional role of estriol.

Dr. Phillippe stressed that the exploration of mechanisms underlying parturition is only beginning and that it heralds a new era. "If you ask me where the biology of obstetrics is going, I'll tell you genetics and molecular biology" he said.
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Author:GOLDMAN, ERIK L.
Publication:OB GYN News
Geographic Code:1USA
Date:Nov 15, 1999
Words:852
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