Sex hormone metabolite reduces stress, anxiety in female rats

A steroid hormone released during the metabolism of progesterone, the female sex hormone, reduces the brain’s response to stress, according to research in rats by scientists at Emory University School of Medicine, the Yerkes National Primate Research Center and Atlanta’s Center for Behavioral Neuroscience. The scientists found evidence that the progesterone metabolite allopregnanolone reduces the brain’s response to corticotropin-releasing factor (CRF), a peptide hormone that plays an important role in the stress response in animals. The finding, which was reported in the Nov. 10, 2004 edition of the Journal of Neuroscience, could provide a new drug target for treating anxiety and depression in women.

In the study, Emory researchers Donna Toufexis, PhD, Michael Davis, PhD and Carrie Davis, BS, and Alexis Hammond, BS, of Spelman College, compared how female rats with different levels of the sex hormones, estrogen and progesterone, reacted to loud noises after injections of CRF into the brain’s lateral ventricles. CRF injections usually increase the “acoustic startle response” in this test used to gauge stress and anxiety, a phenomenon called CRF-enhanced startle.

In the first experiment, the scientists compared acoustic startle responses after CRF injection in an estrogen-only group, an estrogen-plus-progesterone group and a control group that did not receive any sex hormones. All the rats lacked ovaries and the ability to produce sex hormones naturally. Acoustic startle response was unaffected in the estrogen-only group and the control group. In the estrogen-plus-progesterone group, however, CRF-enhanced startle was significantly lower than in the other groups.

In another set of experiments, the researchers discovered that lactating female rats with naturally high levels of progesterone had markedly lower CRF-enhanced startle responses compared to virgin females with intact ovaries. “Findings from theses initial experiments pointed toward the conclusion that progesterone inhibits the effect of CRF on the acoustic startle response,” said Toufexis.

To test this hypothesis, the researchers gave only progesterone to female rats lacking ovaries, then compared the acoustic startle response to female rats without ovaries injected with corn oil. The progesterone group displayed significantly lower CRF-enhanced startle responses. When ovariectomized females were tested with allopregnanolone alone it also reduced CRF-enahnced startle.

In a final experiment, the scientists compared the effects on females that received progesterone with those that received medroxy-progesterone, an artificial progestin that binds to progesterone receptors but does not metabolize into the progesterone metabolite allopregnanolone. Only natural progesterone reduced CRF-enhanced startle.

Previous studies have determined that allopregnanolone enhances the activity of GABA, the main inhibitory neurotransmitter in the central nervous system, at its receptors throughout the brain. This mechanism, Toufexis said, likely accounts for progesterone’s blunting effect on the brain’s stress system.

Findings from the study correlate with clinical evidence that some people suffering from depression or anxiety have low allopregnanolone levels that normalize after treatment with anti-depressant medications.

“New drugs could potentially be developed that mimic the effect of allopregnanolone on the GABA receptor, providing a new approach for controlling mood disorders in women,” said Toufexis. “The next step is to determine where exactly allopregnanolone is working in the brain to reduce the effect of CRF.”