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Dr. Ayman Al-Hendy

Researchers at Meharry Medical College have played a prominent role in two recent discoveries impacting women’s reproductive health, showing great promise for future therapy options to combat premature ovarian failure and to reduce the risk of preterm labor.

Dr. Ayman Al-Hendy, the scientific director of the Meharry Center for Women’s Health Research (see sidebar), is at the helm of both studies. Al-Hendy, who is also vice chair of the Department of Obstetrics and Gynecology at Meharry, relocated to Nashville seven months ago from his post at the University of Texas Medical Branch. Researchers at both schools contributed to the published findings.



Combating Premature Ovarian Failure (POF)

“Premature ovarian failure, by definition, is when women stop having their periods before the age of 40,” Al-Hendy said. “The average age of menopause in the United States is 52.”

For the 1-2 percent of the population who suffer from POF, the residual effect typically isn’t as traumatic for women who have completed their families. Unfortunately, Al-Hendy noted, many of the women with premature ovarian failure are often in their late teens or twenties.

“These women have no chance of achieving pregnancy,” he said, adding that the failure is two-fold in that the ovaries no longer produce hormones or eggs. “At the moment, there is no effective treatment for this condition.”

Al-Hendy added that physicians can supplement with hormones to temper the menopause symptoms but cannot assist the women in conceiving a biological child.

“The reason for premature ovarian failure was not known until recently. A specific gene mutation has been identified,” he explained of a 1995 discovery out of Finland that found a mutation (566CàT) that blocks the normal function of the follicle-stimulating hormone receptor (FSHR).

Using human ovarian cells in the lab, Al-Hendy and his colleagues found they were able to correct for the mutation.

“We used a virus vector to introduce the normal FSHR gene, and when we did this in the cell lines from the premature ovarian failure patients, we were able to get these cells to produce normal levels of hormones and to function in a normal fashion, suggesting that when we move forward into the mouse model and eventually into POF women, we expect to be able to produce normal ovulation,” he explained.

Since the team’s findings were reported in Molecular Human Reproduction, Al-Hendy and Meharry researchers have moved on to mouse models.

“After injecting the virus vector directly into the ovaries of these mice, we were successful in reversing the genetic defect,” he said with excitement. Al-Hendy added that the ovaries in the mice produced a normal level of estrogen, and the research team normalized the folliculogenesis process.

This latest round of discovery is currently being prepared for publication as Al-Hendy looks ahead to future research. Ultimately, if the laboratory success could be replicated in patients with premature ovarian failure, the therapy would eliminate the need for donor eggs and the financial and ethical issues with which these women sometimes struggle.

“We’re really excited about this,” Al-Hendy concluded. “This would be the first potential success in helping these women achieve pregnancy of their own biological child in a normal physiological manner.”

Reducing Preterm Births

The second recent discovery from Meharry researchers and their colleagues at the University of Texas Medical Branch is tied to inhibiting the activity of the enzyme catechol-O-methyltransferase (COMT) to reduce the risk of delivery at less than 37 weeks of gestation.

Al-Hendy said that the rate of preterm labor in the United States has not changed much for the past 30 years — holding stable at about 10 percent — until the last decade when the rate actually increased to 13 percent. He calls this state of affairs “negatively impressive.”

During a period of time when medical science has made major inroads in combating many diseases and conditions, he said there simply hasn’t been improvement in effectively reducing preterm births. Furthermore, he noted, the rate of preterm labor in African-American women is about four to five times that of other ethnic groups, including Hispanics and Caucasians.

“Our goal is to understand the biological basis of this ethnic disparity issue, and our goal is to develop better methods to prevent, diagnose and treat preterm labor in all ethnicities,” he stated.

“The cost of taking care of premature babies … or low birth weight babies … is enormous,” Al-Hendy continued. “Some estimates put it at $6 billion a year in the U.S. alone. The long-term outcome of low birth weight babies is far from satisfactory. They have an increased risk of neurological and respiratory disorders,” he said, noting that the quoted healthcare costs are for the immediate care of premature infants and don’t factor in the long-term effects and resulting need for additional care.

“The problem with preterm labor now is we wait until a woman comes in with contractions and then we try to stop the labor. Usually, it’s too late at that point so everyone is trying to find an early biomarker,” he explained.

However, researchers have now established that the COMT enzyme is expressed in the myometrium (uterine wall) in a specific fashion during pregnancy.

“In work done in pregnant rats, we have found the level of COMT is high at the beginning of pregnancy and then tapers off toward the middle of pregnancy and increases again towards the time of delivery,” Al-Hendy reported.

“Interestingly,” he continued, speaking of the discoveries made by his team, “a specific estrogen metabolite level in the urine (2-hydroxy estrogen) was a mirror image of these changes. What we are suggesting is this particular metabolite can be a potential biomarker for the early diagnosis of preterm labor.” He added that the assay is very simple — just a urine test.

The second phase of the Meharry research centers around the next steps to take once a high-risk identification has been made.

“We have found inhibitors of this enzyme — the COMT — are able to reduce the risk of preterm labor in pregnant rats by about 45 percent,” he said.

In the rat study, subjects were given oral medication twice a day with no seeming effect on the fetus. Al-Hendy said that the pregnant rats ultimately gave birth to an average number of pups with no detectable birth defects.

While the potential for easily identifying women at high risk for preterm labor and effectively intervening is exciting, Al-Hendy cautioned that further research is necessary to confirm their animal findings in humans. The Meharry team is collaborating with investigators at Centennial Medical Center on additional research.

If further study confirms the biomarker in humans, a routine urine sample would help physicians identify high-risk patients. Al-Hendy said that effective medicines already exist that help the fetus’ lungs mature in case of preterm labor, which might be indicated in these pregnancies. Furthermore, if the additional research shows equal human success in inhibiting the COMT enzyme, physicians might be able to relax the uterus and prolong pregnancy past 37 weeks.

“The mother’s uterus is the best place for the baby … so the longer the baby stays in, the better off he or she is,” Al-Hendy concluded.



May 2008

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