Pain, estrogen and the brain

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Sorry, it's long...but provides some clues...http://www.sciencedaily.com/releases/2004/10/041030133346.htmGender And Sex Hormones Affect The Brain's Pain Response And More, According To New Studies

ScienceDaily (Nov. 1, 2004)

— Scientists are now uncovering increasing evidence that the brain not

only responds to hormones produced by the reproductive system, but that

these hormones—the so-called "female hormones," estrogen and progestin,

and the "male" androgens, such as testosterone—play an important role

in the development of differences between male and female brains."Understanding the impact of hormones on sex differences in the

brain is important for understanding human health and disease," says

University of Michigan biopsychologist Jill Becker, PhD. "Some

conditions—persistent pain syndromes, such as fibromyalgia and TMJ

(temporomandibular joint syndrome), for example—are more frequently

diagnosed in women than in men. More women than men also suffer from

mood disorders, such as major depression, and anxiety disorders. On the

other hand, more men than women develop alcoholism and abuse drugs."

The study of hormone-related differences between male and female

brains is not as simple as it may seem at first. Straightforward

comparisons of males and females are not possible because of the

cyclical nature of reproductive hormone production in females, Becker

points out. The menstrual cycle in humans and other primates and the

estrous cycle in rats and mice involve constantly changing levels of

reproductive hormones in the blood and in the brain. Furthermore,

although brain development begins before birth, it continues well into

young adulthood, and there is increasing evidence that parts of the

brain continue to grow, die back, and change throughout the life span.

"Reproductive hormones have effects on all of these stages of brain

growth and development," says Becker. "For these and other reasons, the

study of sex differences in the brain is both complicated and

fascinating."

At the University of British Columbia , Liisa Galea, PhD, has been

investigating the contribution of one form of estrogen, estradiol, to

learning and memory. In recent animal studies, Galea and her colleagues

examined the effect of low and high levels of estradiol on working and

reference memory. Working memory, or short-term memory, manipulates and

retrieves information that is needed for a temporary task; it decays

rapidly. Reference memory involves the long-term storage of

information, and is stable over time. "When you remember where your car

is in a shopping center parking lot on any given day, you're using

working memory," explains Galea. "When you find the shopping center

parking lot day after day, you're using reference memory."

In their study, Galea and her colleagues removed the ovaries from

adult female rats (to eliminate naturally produced estrogens) and then

gave the rats various levels of estradiol. "We found that low levels of

estradiol improved the animals' working memory, but high levels

impaired both their working and their reference memory," says Galea. In

addition to modulating forms of learning and memory, estradiol

influences cell growth in many areas of the brain—and, as Galea and her

colleagues have found—estradiol's effects on that growth are different

in the brains of males and females. In recent animal studies, Galea and

her colleagues discovered that high levels of estradiol in females

initially increased, then subsequently suppressed, the production of

new brain cells in the dentate gyrus of the hippocampus, an area of the

brain that is involved in learning and memory and that produces new

neurons throughout life. This same pattern does not appear to be

similar in the male brain. Once the new brain cells were formed,

however, estradiol enhanced their survival differently in males and

females. "In male rats, estradiol enhanced the survival of new cells

only during a discrete period of time," says Galea, "but in females,

the estradiol-induced enhancement of new neurons occurred during all

the time periods tested."

As these and other studies show, estradiol has complex interactions

with learning and memory and with brain cell growth—and these

interactions are different in the brains of males and females. This

work promises to lead to a more complete understanding of the effects

of reproductive hormones in the brain. In particular, it may bring new

insight into the confusing and seemingly contradictory effects of the

use of estrogen by post-menopausal women on learning and memory. It may

also help explain the mechanisms underlying gender differences in

cognition and susceptibility to mental diseases.

At the University of Michigan , Jon-Kar Zubieta, MD, PhD, and his

colleagues have been studying the effect of sex hormones on pain and

stress-response systems in the brain. They have found that differences

between men and women in the perception and experience of sustained

pain—by itself, a physical and psychological stressor—may be due, in

part, to the influence of reproductive hormones on the brain. These

findings promise to lead to a greater understanding of how and why

certain diseases characterized by chronic pain, such as fibromyalgia

and TMJ, occur more often in women than in men.

Zubieta's research has focused on a particular neurochemical pathway

in the brain—the mu-opioid neurotransmitter system—which uses

endogenous chemicals called opioids (commonly known as endorphins and

enkephalins) to send signals between brain cells to suppress the

sensation of pain. When a stressful stimulus, such as sustained

physical pain or severe emotional stress, threatens the well-being of

the body, the brain releases these opioid peptides, which then bind to

receptors (known as mu-opioid receptors) located in various regions

throughout the brain. "The rapid activation of this system suppresses

an individual's perception of a stressful event and the emotions that

accompany it," explains Zubieta, "thus making the pain and stress more

tolerable."

To study the mu-opioid neurotransmitter system, Zubieta and his

colleagues use positron-emission tomography (PET) brain imaging, which

allows them to observe the system in action. Volunteers are scanned

over a period of 20 minutes as they receive a moderately pain-causing

but harmless injection of salt water in their jaw muscle. (The pain

dissipates within minutes of completion of the experiment and causes no

residual damage.) The studies are double-blind and placebo-controlled.

In a study involving 14 men and 14 women, Zubieta found significant

differences in how the brains of men and women respond to pain. The men

experienced an increase in the amount of endorphins released in certain

regions of their brains during the painful state of the experiment,

while most of the women showed a decrease. The participants were asked

to rate the intensity and unpleasantness of the pain. Women

consistently gave higher ratings for both.

All the women in this early study were in the early follicular phase

of their menstrual cycle (shortly after menses) when blood levels of

both estrogen and progestin are low. None were taking hormonal birth

control and all had ovulated the month before. For their latest study,

Zubieta and his colleagues decided to examine whether varying blood

levels of estrogen would modify the response of the mu-opioid system in

women. Using the same jaw pain model, the scientists studied a group of

women during the follicular phase of their menstrual cycle and again

during the same phase in another month—but after the women had been

wearing an estrogen-releasing skin patch for a week. The results were

striking. When estrogen levels were high, the women showed marked

increases in their ability to release endorphins and activate the

mu-opioid receptors—increases that rivaled and even surpassed those of

men. The women also rated the intensity and unpleasantness of the pain

lower than they had when their estrogen levels were low.

"Our studies demonstrate that some of the sex differences in an

individual's response to pain, or, in more general terms, to a

substantial stressor are mediated through specific chemical systems in

the human brain and that these responses are modulated by blood levels

of sex hormones," says Zubieta.

The linking of pain sensitivity and regulation to reproductive

hormones—particularly estrogen—makes some "evolutionary" sense, Zubieta

says. Women require more flexible, adaptive mechanisms to protect

themselves from injury during their reproductive years to preserve the

reproductive function of the species, he says. At the same time, women

also have to adapt to the body changes and pain that takes place during

pregnancy and childbirth—a time when reproductive hormones are at an

all-time high. "So they have to develop mechanisms, like the mu-opioid

neurotransmitter system, that promote that type of flexibility,"

Zubieta says. "Interestingly, this neurotransmitter system is also

involved in maternal-offspring attachment behavior, another area where

estrogens may play a role."

At McMaster University , Meir Steiner, MD, PhD, and his colleagues

have been studying the role that estrogen and other reproductive

hormones may play in gender differences in depression. Women are two to

three times more likely than men to experience a major depressive

episode during their lifetime.

"The underlying cause of the gender difference in depression and

other mood disorders is not entirely clear," says Steiner, "but the

differences, which begin rather dramatically at puberty and become less

marked after menopause, strongly suggest a link to fluctuating estrogen

and progesterone levels." Although hormones fluctuate in both men and

women, the fluctuations are much more pronounced in women, particularly

around their menstrual cycles, during the weeks immediately after

pregnancy (postpartum), and in the period leading up to menopause

(perimenopause). These fluctuations, Steiner has proposed, cause

disturbances along the hypothalamic-pituitary-adrenal axis, a part of

the neuroendocrine system that is believed to play a primary role in

the body's reaction to stress.

Because hormonal fluctuations occur in all women, yet not all women

experience clinical depression, it's likely that women who develop

hormone-related depression and mood disorders have a genetic

predisposition to them, Steiner adds. Further research is needed, he

says, to identify the specific genetic markers that might lead to a

better understanding of how the balance between estrogen, progesterone,

testosterone, and other reproductive hormones affects brain function

and increases women's susceptibility to depression.

In recent animal studies, Craft, PhD, and her colleagues at

Washington State University have found that differences in sensitivity

to pain and opiate analgesia between males and females may be due

primarily to testosterone exposure during early development. Using a

rat model that exhibits particularly dramatic sex differences in

response to opiate analgesia, the researchers manipulated hormones in

rats when the animals were very young and then again when the rats were

adults. The animals' pain thresholds and their response to

morphine-induced analgesia were then evaluated using two different

tests.

Craft and her colleagues found that early testosterone deprivation

increased pain sensitivity in males, making them more like "normal"

females. Surprisingly, this effect could be reversed with only two

weeks of testosterone treatment during adulthood. Females given

testosterone as neonates showed different pain thresholds than

untreated females—in other words, they became more like "normal" males.

Unlike with the male rats, however, giving the female rats testosterone

supplements in adulthood had no further effect.

"These results suggest that differential pain sensitivity in adult

male rats compared to females is primarily due to testosterone exposure

during development," says Craft.

Early testosterone exposure also influenced the rats' sensitivity to

morphine-induced analgesia when they were adults. The males deprived of

testosterone as neonates were less sensitive to morphine than normal

males (i.e., more like "normal" females), and the females given

testosterone as neonates were more sensitive to morphine than control

females (i.e., more like "normal" males). Interestingly, the effects of

neonatal testosterone deprivation in males could be reversed in some

tests simply by exposing the males to testosterone for two weeks during

adulthood. In contrast, females exposed to testosterone soon after

birth and then again in adulthood showed no further effect from the

later exposure.

"Thus, it can be concluded that testosterone exposure before birth

or on the first day after birth is sufficient to enable males to regain

their `male phenotype' as long as they are exposed to testosterone in

adulthood," says Craft, "whereas exposing females to testosterone soon

after birth is insufficient to completely change them into the male

phenotype in terms of their sensitivity to pain and to morphine-induced

analgesia."

Craft and her colleagues are now attempting to replicate their

findings in other strains of rat. "Overall, our current results suggest

that adult females' greater sensitivity to pain and lesser sensitivity

to the pain-killing effects of morphine will be difficult to ameliorate

by simple hormone treatment—with testosterone, for example—in

adulthood," says Craft. "Instead, these sex differences would appear to

be determined very early in development."