The Corpus Callosum

Sarah Berga, et. al. presented a paper at the European Society of Human Reproduction and Embryology conference in Prague, about the use of cognitive-behavioral therapy for treatment of infertility.  It this post, I elaborate on some of the details that the mainstream media left out.  I end by speculating about what it might mean about our society, that such a simple solution could have been overlooked for so long.

From a report on the Times Online:

Learning how to beat stress could be the best fertility treatment
by Mark Henderson, Science Editor
June 21, 2006

A study into the effects of therapy offers new hope to thousands of women

STRESS may be one of the main causes of female infertility, preventing thousands of otherwise healthy women in Britain from starting a family.

Many women who struggle to conceive could increase their chances greatly by learning to cope more effectively with the stress of daily life, scientists said yesterday.

Research in the United States has shown that psychological treatment designed to relieve stress can achieve spectacular results, restoring fertility to women who do not ovulate or menstruate. [...]

In Professor Berga’s study, 16 women aged between 20 and 35 with stress-related amenorrhea, none of whom had had a period for at least six months, were split into two groups. One group was observed but not treated, while the other eight women were given a 20-week course of cognitive behavioural therapy, a “talking treatment” in which strategies for coping with stress are taught.

“A staggering 80 per cent of the women who received CBT started to ovulate again, as opposed to only 25 per cent of those randomised to observation,” Professor Berga said.

The study had a small sample size, not unusual for a paper of this sort, but still it is a factor that limits the generalizability.  Perhaps more importantly, the study only involved women with "stress-related amenorrhea."  Presumably, this refers to functional hypothalamic amenorrhea, a condition in which the normal pulsatile release of GnRH is disrupted, often with an apparent stressful antecedent.


structure of GnRH

What this means, is that the study may not apply to the majority of women with infertility, but it could turn out to apply to a sizable  fraction.  About 10% of women are infertile (from all causes combined) at any single point in time, and about 5% of women develop functional hypothalamic amenorrhea at some point in their lives.   From an earlier article about Dr. Berga's work:

Called functional hypothalamic amenorrhea (FHA), the condition affects some 5 percent of women in their reproductive years. It is characterized by wildly irregular or absent periods -- often for as long as two years or more.

As I mentioned before, FHA often involves a disruption in the normal pulsatile release of GnRH.  This means that all of the components of the reproductive system are working, in that all the reproductive organs are intact, and all of the tissues that are supposed to secrete hormones are capable of doing so.  The only problem is that the clock that determines when a key hormone is supposed to be released, is not working right.  It is a very subtle problem, but it has significant consequences.  

The regulation of GnRH secretion is complex.  The following is from an online endocrinology textbook.  Skip it unless you are fascinated by the subject, or unless you are a medical student, in which case you are expected to memorize everything:

As with most neurosecretory hormones, the GnRH pulse generator localized in the arcuate nucleus is modulated by input from other neuronal systems. Animal studies have shown that neurotransmitter agents such as dopamine, norepinephrine, and serotonin can regulate GnRH or LH secretion. These studies suggest that activation of the noradrenergic system is associated with increased release of GnRH whereas dopaminergic or serotonergic activation can either inhibit or stimulate GnRH release , . These observations can explain in part the CNS-associated disruption of normal menstrual cycles in patients who take phenothiazines (dopamine receptor antagonists), stimulants, antidepressants, and sedatives on a chronic basis.

Excitatory amino acids such as glutamate and aspartate have recently been shown to be localized to the arcuate nucleus in the media basal hypothalamus adjacent to GnRH neurons and have been implicated in a regulatory role for GnRH secretion primarily during pubertal maturation . These two amino acids appear to activate GnRH secretion during puberty in monkeys.

Endogenous opiates peptides such as endorphins, enkephalins, and dynorphins appear to play largely an inhibitory role in GnRH and LH secretion. In patients with hypothalamic amenorrhea, blockade of endogenous opiate receptors with receptor antagonists such as naloxone or naltrexone will induce an increase in pulsatile release of GnRH and LH . Long term treatment of hypothalamic amenorrhea patients with naltrexone can result in return of normal menstrual cycles in some individuals. These findings indirectly suggest that endogenous opiate activity is suppressing GnRH secretion.

In case you skipped the technical stuff, I'll summarize:  regulation of the main hormones that control the menstrual cycle comes from the pituitary.  The pituitary is controlled by the hypothalamus, which is part of the brain.  The hypothalamus is controlled by input from a variety of sources.  The transmitters involved include dopamine, serotonin, norepinephrine, endorphins, glutamate, and aspartate.  

It follows that a profound dysfunction in any of those transmitter systems can have an effect on fertility.  Stress, of course, can affect many of those transmitter systems.  So it would not be terribly surprising to find that stress can have a negative effect on reproduction.  

One irony here, is that infertility is often treated by massive doses of hormones.  That in itself can be stressful.  (If that is not obvious, take my word for it, or better yet, talk to someone who's been through it.)  So in a way, hormone treatment is inherently an uphill battle.  You may succeed in forcing some on the hormones to do what the textbook says they should do, but in so doing, you actually add to the stress that probably is the root of the problem to begin with.  

So, I do not know how what the response rate would be, if cognitive-behavioral therapy were tried for the entire population of women with FHA, but it sure would be nice if it turned out that a simple, elegant, and inexpensive treatment could eliminate the need for much of the expensive and stressful hormone treatment that currently is being used.  

I know from prior experience working in an eating disorder clinic, that some women with eating disorders have difficulty attaining pregnancy, and some undergo hormone treatment.  It always seemed obvious to me that such treatment was not only unnecessary, but it was unnecessarily risky.  What the person needed to do, was to eat properly, manage stress, and back off on the compulsive exercise, not take a ton of hormones.  Those were extreme cases.  What Berga's work shows, is that the same can be true for less extreme cases as well.  

Looking at it from another angle, it could be interesting to figure out what it is about our society that led us to pursue a complex, invasive, high-tech solution, when a simpler and less intrusive solution was right there to begin with.  You don't suppose it could have anything to do with a paternalistic attitude among physicians, do you?