Richard G. Petty, MD

Hormones, Addictions and Mood

People working with mental illness have been for years now been puzzled by two observations. The first is that mood disorders and schizophrenia follow quite different trajectories in men and women. Women tend to be more vulnerable to mood disorders and if they get schizophrenia it tends to be less severe and to have fewer “negative” symptoms, such as flat, blunted or constricted affect and emotion, poverty of speech and lack of motivation until after menopause. We have looked at some of the reasons for the different rates of mood disorder, in terms of relationships and social pressures, but there must also be a biological component. The second puzzle is that women are more vulnerable to addictive drugs in the days before they ovulate.

New research published in the Proceedings of the National Academy of Sciences may provide part of the answer to both puzzles.

Colleagues at the National Institute of Mental Health (NIMH), a component of the National Institutes of Health (NIH), have conducted a fascinating imaging study that has shown that fluctuations in levels of sex hormones during women’s menstrual cycles affect the responsiveness of the reward systems in the brain.

The reward system circuits include the:

  • Prefrontal cortex, which has key roles in thinking, planning and in the control of our emotions and impulses
  • Amygdala, which is involved in rapid and intense emotional reactions and the formation of emotional memories
  • Hippocampus, which is involved in learning, memory and navigation
  • Striatum that relays signals from these areas to the cerebral cortex

It has been known for some time that neurons in the reward circuits are rich in estrogen and progesterone receptors. However, how these hormones influence reward circuit activity in humans has remained unclear.

The researchers used functional magnetic resonance (fMRI) imaging to examine brain activity of 13 women and 13 men while they performed a task that involved simulated slot machines. The women were scanned while they did the task, both before and after ovulation.

When anticipating a reward, in the pre-ovulation phase of their menstrual cycles the women showed more activity in the amygdala and frontal cortex. When women were actually winning prizes, their reward systems were more active if they were in the phase of their menstrual cycle preceding ovulation. This phase of the cycle is dominated by estrogen, compared to postovulatory phase when estrogen and progesterone are both present. When winning, the main systems that became active were in the parts of the brain involved in pleasure and reward.

The researchers also demonstrated that the reward-related brain activity was directly linked to levels of sex hormones. Activity in the amygdala and hippocampus was in directly linked to estrogen levels, regardless of where a woman was in her cycle. When women won prizes during the post-ovulatory phase of the cycle, progesterone modulated the effect of estrogen on the reward circuit.

Men showed a different activation profile from women during both anticipation and delivery of rewards. Men had more activity in the striatum during anticipation compared with women. On the other hand, women had more activity in a frontal cortex when they won prizes.

This research could have a number of important implications. The most obvious is that it confirms what many women know already: they are more likely to take addictive substances or to engage in pleasurable – but perhaps impulsive or risky – behaviors just before they ovulate.

It is not difficult to imagine why this might have developed during evolution.

“Coming to terms with the rhythms of women’s lives means coming to terms with life itself, accepting the imperatives of the body rather than the imperatives of an artificial, man-made, perhaps transcendentally beautiful civilization. Emphasis on the male work-rhythm is an emphasis on infinite possibilities; emphasis on the female rhythms is an emphasis on a defined pattern, on limitation.”
–Margaret Mead (American Anthropologist and Writer, 1901-1978)

When Is It An Illness?

There’s been a very worrying trend in recent years, and that is constantly to medicalize every kind of behavior: we are no longer allowed to be shy, we have to be “socially phobic;” many things once regarded as vices, like excessive gambling, drinking or eating are now being re-cast as impulse control disorders and adolescent temper tantrums could be “Intermittent explosive disorder.” And I now read a report about giving selective serotonin reuptake inhibitors (SSRI) antidepressants to people with emotional lability.

In April of this year the Public Library of Science published a series of articles on the important topic of “disease mongering,” which two authors define as “the selling of sickness that widens the boundaries of illness and grows the markets for those who sell and deliver treatments.” The authors made the point that some of the medicalization of human behavior is being driven by some pharmaceutical companies. They picked on several conditions or illnesses in which claims of prevalence and severity have been inflated in order, they claimed, to generate a need for medicines. One of their targets was female sexual dysfunction, where there has been a serious attempt to convince the public in the United States that 43% of women live with this condition. Many experts have heavily contested those figures.

One of the big worries about expanding the boundaries of an illness is that it is easy to throw out the baby with the bathwater. To use this last example: saying that the figures for female sexual "dysfunction" are inflated can lead some clinicians to dismiss everyone who has a problem, and then not to treat people with genuine organic difficulties. It is tragic to see people referred to a psychiatrist for a physical problem like low testosterone or undiagnosed diabetes or thyroid disease.

There can also be marked differences of opinion about the nature of illness. “Premenstrual dysphoric disorder,” (PMDD), is a particularly severe premenstrual syndrome, with some additional mood features. The American Psychiatric Association has precise diagnostic criteria for PMDD. The regulatory authorities in the European Union decided that this was not a real illness and declined to let a pharmaceutical company market a medicine for it.

I’m all for doing anything that I can to help people and to alleviate suffering. Part of the problem is that it is acceptable to have a “disorder.” The prevailing attitude is that no one can be blamed for being sick. The reality is that by most estimates, 70% of human illness is caused by lifestyle choices. By turning everything into disorders we take away our responsibility for our actions.

Most people are not looking for the causes of their troubles, they want a quick fix. Changing is hard, it is inconvenient and it is much easier to believe a pill will make everything better.

The second issue is that “better living through chemistry” may not be. There’s been a question rumbling round for some time now: has the over-exposure of young people to antibiotics, analgesics and sleeping tablets, been partly responsible for the rise in asthma and in substance abuse in later life? We don’t know the answer but it is important for us to think about.

The third point is that we need to think about what we are doing to ourselves if we want to medicate our way to happiness. Do we really want to deny ourselves the opportunity for becoming happy by our own actions rather than relying on a pill and being told what is normal?

P.S. Four years ago the Nuffield Council on Bioethics produced an important report entitled Genetics and Human Behaviour: the Ethical Context. It looked at some of the ethical challenges that are coming with the constant new discoveries in biology, and warned against the dangers of widening diagnostic categories, to encourage the use of medication by people who would not necessarily be thought of as exhibiting outside the normal range. It is well worth reading.

Migraine and Hormones

Migraine (can be a frightfully difficult problem to treat. It is such an interesting puzzle, that the first book that I ever wrote was on migraine and other types of headache. Migraine is a great deal more than just a severe headache. It is can also be associated with neurological symptoms, and people often become exquisitely sensitive to light and sound. Additionally, at the beginning of the attack, the stomach stops working properly, which can make the absorption of medicines very difficult. Then comes the vomiting and sometimes diarrhea.

Although migraine is usually described as a “vascular” headache, there are strong reasons for thinking that it is more than that. People who suffer from the classic type of migraine often have spreading visual problems or partial visual loss, which goes on for between ten and sixty minutes. These visual problems are likely the result of a spreading wave of neurological depression spreading over the visual cortex at the back of the brain. The sensitivity to light and sound suggests that something is going wrong in the neurological systems that normally filter sensations, and the gastrointestinal problems indicate that something is going wrong in some of the control centers of the brain. There are some real oddities about migraine: it is exceptionally uncommon in people with diabetes; appears to be slightly more common in people who are left handed and is one of the only illnesses that tends to gets better as we get older.

There are a number of well-known triggers to migraine attacks. Though the scientific literature on triggers is not conclusive, here are some of the more common ones, that if avoided, have helped a great many people:

  • Stress (either during stress, or when the pressure comes off)
  • Cheese
  • Chocolate
  • Coffee
  • Citrus fruit
  • Red wine
  • Changes in the weather (especially when there are a lot of positive ions in the atmosphere)
  • Mono-sodium glutamate (MSG)

One of the best-known features of migraine is that it is considerably more common in women and that there is often a relationship between headaches and phases of the menstrual cycle, in particular during the pre-menstrual days. There have been many small studies that have indicated that oral contraceptives might increase the risk of suffering from migraine. A new study from Trondheim in Norway, has confirmed a link between oral contraceptive and migraine. The Nord-Trøndelag Health Study was done between 1995 and 1997. It included 14,353 pre-menopausal women, of whom 13,944 (97%) responded to questions regarding their use of contraceptives. There was a significant association between migrainous and non-migrainous headaches and the women’s reported use of estrogen-containing oral contraceptives. An important finding was that there was no relationship between the number of headaches and the amount of estrogen in the contraceptive pill.

There is one more thing to factor into the equation. Over the last two decades, there have been many reports of an association between certain types of migraine and cerebrovascular accidents (“strokes”). In the largest analysis of the data, that was published in the British Medical Journal, there was indeed a higher rate of strokes in women who had migraine and who were taking oral contraceptives. These studies included some of the older ones done in the days when the doses of hormones were higher than they are today, but when making decisions, it is important to be aware of this rare association.

An editorial in the British Medical Journal made these recommendations, with which I agree:

1. In an otherwise healthy young person, there is little cause for concern because the absolute risk of stroke is very low.

2. People with migraine who are on oral contraceptives have another reason for not smoking

3. Use low dose estrogen or progesterone only contraceptives in young women with migraine.

4. Although there isn’t much good evidence, many neurologists suggest stopping oral contraceptive pills if the migraine becomes more frequent or changes in character.

5. The risk of stroke gradually increases over age, particularly in smokers, so a slightly older smoking woman with migraine, should probably not be taking an oral contraceptive, unless it is the only option for her.

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