Autoimmune Thyroid Disease

An Unfortunate and Lengthy Adventure in Misdiagnosis

The New Scientist on pain

with 7 comments

I highly recommend a subscription to the excellent New Scientist magazine. Every week there’s something great in there. Here are two articles about the differing male and female perception of pain, very interesting, if, like me, most of your symptoms are chronic pain symptoms.

JON LEVINE was just testing painkillers on people who’d had a wisdom tooth extracted, when he uncovered rather more than he’d bargained for. The women in his study group found that strong painkillers related to morphine, called kappa-opioids, were most effective at numbing pain. But the same drugs didn’t work for the men at all. “In fact, the doses used in the clinical trial made pain worse for men,” says Levine, a clinical neuroscientist from the University of California in San Francisco.

He was shocked. “The idea that a therapy that had been around for decades could affect women and men in such dramatically different ways was anathema,” he says. “It was such an incredible mindset in the field of pain, missing what had clearly gone on in front of their eyes for years.”

It’s not an effect specific to opioids, either. Another recent study showed that ibuprofen, a widely used anti-inflammatory drug, can be much less effective for women than for men. Researchers at the University of New South Wales found that when they used mild electric shocks to induce pain in healthy young people, only the men got any relief with ibuprofen. It was only a small study, but still worrying, as the drug is often marketed with women in mind.

It’s been five years now since Levine first spotted a sex difference, yet we still don’t really understand why it exists. And when it comes to testing or prescribing painkillers, or studying pain, nothing much has changed. Remarkably, even many of those involved in pain research are unaware of these findings. “I myself have never been able to get relief from ibuprofen and now I understand why,” says Marietta Anthony, a pharmacologist at Georgetown General Clinical Research Center. “This is very dramatic, and has a direct impact for the clinic.”

There have always been playful stereotypes of how men and women suffer pain differently. Women are more delicate—but endure childbirth. Men are stoical—until they see a dentist’s chair. But these few studies show there’s more to the caricatures than meets the eye. Real differences in the underlying biochemistry of male and female pain are revealing themselves. The differences are also starting to suggest some surprising strategies for sex-specific painkillers.

It’s perhaps no surprise that the differences have eluded scientists for so long. Pain is multidimensional and highly subjective, and therefore very difficult to study. It varies with the time of day, age, diet, stress, genetic background, location, past and present injuries, and in women, reproductive status and the menstrual cycle.

But not only that. Only 10 years ago, pharmaceutical compounds were tested almost exclusively on men. Women were left out of tests in case their inconveniently fluctuating hormones messed up the analysis. The testers also feared harming a pregnant woman’s fetus, while ignoring the obvious safeguard of a pregnancy test and contraceptives.

Only in 1993 did the US make it a legal requirement for women to be included in clinical trials. According to a recent report, on average, 52 per cent of subjects in large-scale trials are women. This looks like progress—but it’s not. This figure includes women-only studies such as those investigating hormone therapies or drugs to treat breast cancer. And when testing medications for diseases common to both sexes, women’s and men’s results are often still lumped together, burying any differences in a statistical quagmire.

In Britain, things are not much better. The Department of Health advises that gender should be taken into account when determining whether a medicinal product is safe and effective. But how strictly this advice is heeded is anyone’s guess.

To Marietta Anthony, who was previously acting deputy director of the Office of Women’s Health at the FDA, change is imperative. If a drug works differently in men and women, this information should be displayed clearly on the label. “Side effects and efficacy really are different in men and women,” says Anthony, “[and] there may be a very fundamental biological reason.”

One of the more obvious biological reasons is that men and women tend to suffer from different disorders, mostly the result of a complex bag of hormones, reproductive status and anatomy (see Diagram). So differences in how women and men report feeling pain have often been dismissed as being solely down to the pain’s different origins. But origins aside, there’s growing evidence that even when the source is the same, the biochemical signals, nerve connections and the way the brain handles pain are all quite different in the two sexes.

Sex hormones are one reason for the differences in pain perception. Women always cry “ouch” first. Whether it’s in the clinic or the lab, using the heat of a small laser, the pressure of a tourniquet or electrodes placed on the skin, women are less tolerant of pain. But women’s pain sensitivity also yo-yos throughout the menstrual cycle, and just before a period, pain thresholds take a dive. “There is a view that oestrogen is excitatory and could enhance pain transmission in the peripheral nervous system, the spinal cord and in the brain,” explains Roger Fillingim from the University of Florida at Gainsville.

Progesterone has quite the opposite effect: it dampens the nervous system’s response to any nasty stimulus. And it’s most obvious during pregnancy. When progesterone levels rocket in the third trimester, they induce a state of profound analgesia in preparation for labour. Indeed, these hormonal influences are being turned to medical advantage (see “Make your own Valium”). The rest of the time—when not pregnant—women’s tolerance generally remains below that of men.

Levine was one of the first to get an inkling of how sex hormones might be setting men’s and women’s pain thresholds at different levels. His team found that women consistently reported more severe pain than men after removal of a wisdom tooth. Since inflammation is known to underlie most aches and pains, Levine decided to investigate whether inflammatory signals differed between sexes. He gave oestrogen to castrated male rats, and found their pain tolerance plummeted to female levels. And giving testosterone to sterilised females gives them masculine tolerance. In other words, if you switch the sex hormones around, you switch their pain sensitivity around too.

Looking deeper into the biochemical pathways, he has recently found that sex hormones alter the chemical signals involved in inflammation and tissue repair. The female hormone oestrogen quenches the production of bradykinin—a potent inflammatory mediator that protects injured tissues. He believes these differences might account for the different responses to opioids seen in his trial. “As difficult as it is for many of us to acknowledge differences other than in reproductive function, there really are differences between men and women,” says Levine.

Another curious difference caused by our distinct physiology is that—especially in women—the visceral organs “talk” to each other, so that pain in one internal organ can be triggered or enhanced by pain in another. Maria Adele Giamberardino at the University of Chieti, Italy, first noticed this effect in women with kidney stones. She has found that when women have painful periods—a condition called dysmenorrhoea—the typical searing back pain from the urinary tract caused by the stones is much more vicious.

Giamberardino’s findings ring true to pain specialists. In the clinic, both men and women who suffer from chronic conditions such as irritable bowel syndrome often also experience fibromyalgia, headaches and chronic pelvic pain. But this coexistence of painful disorders is greater in females than in males. Giamberardino’s hypothesis is that the female reproductive organs are highly interconnected with the other organs, and that pain in one organ may trigger painful conditions in others that have linked nerve supplies. The flipside is that these links could become new avenues for treating pain. By tapping into the same communication channels, treating period pains, for example, might help to alleviate other aches.

Our different reproductive organs can also lead to differences in how our diet affects pain ratings, says Beverly Whipple, a neurophysiologist and obstetric nurse from Rutgers University in New Jersey. She noticed that Hispanic women seemed to experience more pain during labour, and at first she attributed this to culture. “I told my students that these women were just more comfortable expressing their pain.” Then she became aware of studies in which neonatal rats injected with capsaicin—the chemical that gives chilli its hot bite—did not experience a certain pain-blocking effect that females normally get when pressure is applied to the cervix. Could a diet rich in hot peppers be interfering with the Hispanic women’s natural analgesia?

To find out, Whipple set up a study with Mexican women whose consumption of chillies ranged from one or two a week to three a day. “We found that the women who ate a diet high in hot chilli peppers do not get the pain-blocking effect,” she says.

The physiological differences don’t stop at our reproductive organs and hormones, however. They run all the way to the brain. In a study soon to be published, Anthony Jones, director of the human pain research group at the University of Manchester, has scanned the brains of people experiencing pain from a variety of natural causes. Although many parts of the brain are engaged when a person is in pain, Jones pinpointed one main area of disparity between the sexes. “Women tend to process pain more in one part of the brain concerned with attention and emotion,” he says. He suggests that the experience of pain is bound to differ between men and women. “Women tend to process things in a more affective way,” he says. For women, pain depends on how much attention they pay to a tender spot. So when it comes to treatment, for women it may be as important to provide them with distractions, coping mechanisms and psychological care as painkilling drugs.

Distractions may work in a different way for men. It seems to be important for men to act tough in public. In experiments performed at the State University of New York, Fredric Levine and Laura Lee De Simone found that men’s pain thresholds soared if an attractive female technician was conducting the tests. Women, however, seemed immune to the charms of hunky men. And according to Knox Todd, a specialist in the assessment and treatment of pain at Emory University in Atlanta, Georgia, the differences make their way into the clinic. “What we see in the emergency department is that males make a public display of stoicism, ask for no pain medication, and keep up a good public front.” But their stoicism evaporates as soon as men leave the hospital to go home, he says.

But who wins out in the end? Is having a higher pain threshold good or bad? To women, pain is a wake-up call to sort out the problem before it gets too big. Men, who can put up with more, postpone asking for help until it’s too late. Women’s prompt action could be at least part of the key to their longer life expectancy. In the meantime, a message to dithering males: stop procrastinating, make that dental appointment, and your niggling shoulder pain might get sorted into the bargain. And to overdue pregnant women: ignore the advice that a curry will bring on labour. Chillies are the last thing you need when the contractions kick in.

* * *

Make your own Valium

Sex hormones might complicate our understanding of pain, but one day they might help us beat it, too. Locked inside your brain is the most powerful sedative, anti-anxiety drug and painkiller rolled into one. This magical compound derives from the sex hormone progesterone and, if medicinal chemists get it right, it may soon lead to an analgesic to rival morphine.

Scientists have known since the 1940s that progesterone—the female hormone we usually associate with the Pill and making babies—is also an incredibly potent sedative. Now researchers have found that it is the breakdown products of progesterone that have such a potent anaesthetic and analgesic effect. “During pregnancy, for example, as a woman comes close to term, the levels of these breakdown products of progesterone are extremely high,” says Jeremy Lambert, a neuropharmacologist at the University of Dundee in Scotland. Only the natural hormone will do—the synthetic compounds used in contraceptive pills do not work in the same way.

Fortunately, this natural analgesia and anxiolysis is not exclusive to women. There are enzymes in the brain and spinal cord of both men and women that produce similar breakdown compounds, known as neurosteroids, from cholesterol or progesterone. In mounting doses, they may act as analgesics, anticonvulsants and even anaesthetics.

Researchers are now intent on harnessing these effects. The trick is to untangle one neurosteroid action from another: to induce pain relief without knocking you unconscious and without affecting fertility. Colin Goodchild, an anaesthesiologist at Monash University in Victoria, Australia, may have already hit on a compound—alphadolone—that can do exactly that. “It can work as a pain-relieving drug without causing sedation,” says Goodchild.

Goodchild hopes that alphadolone may eventually replace opioids such as morphine, or at least reduce their usage. Progesterone metabolites might also lead to an “all-natural” sleeping pill and antiepileptic with few, if any, side effects. “I think neurosteroids are going to be the pharmaceuticals of the future,” says Goodchild. His pain, her pain, 19 January 2002, New Scientist


ANYONE in a long-term relationship will tell you that, at times, men are indeed from Mars, and women are almost certainly from Venus. It’s common knowledge that the sexes often think very differently, but until recently these differences were explained by the action of adult sex hormones or by social pressures which encouraged males and females to behave in a certain way. For the most part, the basic architecture of the brain, and its fundamental workings, were thought to be the same for both sexes.

Increasingly, though, those assumptions are being challenged. Research is revealing that male and female brains are built from markedly different genetic blueprints, which create numerous anatomical differences. There are also differences in the circuitry that wires them up and the chemicals that transmit messages between neurons. All this is pointing towards the conclusion that there is not just one kind of human brain, but two.

It’s giving neuroscientists something of a headache. Most of what we know about the brain comes from studies of male animals and male human volunteers. If even a small proportion of what has been inferred from these studies does not apply to females, it means a huge body of research has been built on shaky foundations. Working out exactly how women are different could explain some long-running mysteries, such as why men and women are prone to different mental health problems and why some drugs work well for one sex but have little effect on the other.

It has long been known that some differences exist between male and female brains, but they were widely believed to be restricted to the hypothalamus, which is involved in regulating food intake and controlling sex drive, among other things. Unless they were studying the hypothalamus, researchers generally avoided using female animals in their experiments because the ups and downs of oestrogen and progesterone during the female menstrual cycle made interpreting results more complicated. So, hypothalamus aside, neuroscientists continued to believe that male and female brains were the same.

But it’s becoming obvious that the hypothalamus is only the beginning of the story. For a start, the relative sizes of many of the structures inside female brains are different from those of males. In a 2001 study, Jill Goldstein of Harvard Medical School and colleagues measured and compared 45 brain regions in healthy men and women. They found that parts of the frontal lobe, which houses decision-making and problem-solving functions, were proportionally larger in women, as was the limbic cortex, which regulates emotions. Other studies have found that the hippocampus, involved in short-term memory and spatial navigation, is proportionally larger in women than in men, perhaps surprisingly given women’s reputation as bad map-readers. In men, proportionally larger areas include the parietal cortex, which processes signals from the sensory organs and is involved in space perception, and the amygdala, which controls emotions and social and sexual behaviour. “The mere fact that a structure is different in size suggests a difference in functional organisation,” says neurobiologist Larry Cahill at the University of California, Irvine.

Cahill has found evidence that sex also influences how some brain regions are used. In brain-imaging experiments, he asked groups of men and women to recall emotionally charged images they had been shown earlier. Both men and women consistently recruited the amygdala – a pair of almond-sized bundles of neurons which make up part of the limbic system – for the task. However, the men enlisted the right side of it, whereas women used the left. What’s more, each group recalled different aspects of the image. The men recalled the gist of the situation whereas the women concentrated on the details. This suggests men and women process information from emotional events in very different ways, using different mechanisms, says Cahill.

The same may be true for the brain circuits used to dampen pain. It is well known that women are more likely to seek help for chronic pain than men. Some of this can be chalked up to the fact that women use healthcare services more than men, but even taking this into account, there’s strong evidence that women – and female animals – experience more pain than males. Not all studies show sex differences but, when they do, it’s always the females that feel more pain.

Anne Murphy at the University of Georgia in Athens is trying to find out why chronic pain affects women more than men. She is particularly interested in a pain-suppressing circuit that links two parts of the brain – the periaqueductal grey (PAG) and the rostral ventromedialRVM) – with the spinal cord. When this circuit is activated by a pain signal it can dampen pain by setting off a chain reaction that leads to the release of endorphins, which bind to opioid receptors and inhibit the pain signal. medulla ( “This circuit is the Mecca of pain modulation in humans and all vertebrates, yet no one has asked how it is organised in females,” says Murphy.

There is no clear answer yet, but Murphy’s investigations have yielded some intriguing results. Females have a denser connection between PAG and RVM than males, yet Murphy’s work suggests that this pathway is not activated in females to suppress pain. “This pathway is obviously not being used for pain in females, so what’s the function for it and why is it so much bigger?” she asks.

That question remains unanswered for now, but Jeff Mogil at McGill University in Montreal, Canada, thinks he may have found at least part of the female pain circuitry. In experiments in mice, he chemically blocked a particular receptor found on neurons in the mouse PAG and spinal cord. Mogil discovered that male mice use these N-methyl-D-aspartate (NMDA) receptors to dampen pain, but that blocking this pathway had little impact on females’ ability to deal with pain. “It suggests that females have a separate pathway that doesn’t involved the NMDA receptor,” he says.

Genetic experiments in mice have since led him to suspect that female pain inhibition may be linked to sex-specific variations in the gene for the melanocortin-1 receptor (Mc1r), which regulates hair and skin colour in humans and is also expressed in the PAG. Female mice that lacked a functional version of these genes were less able to block pain, as were female human volunteers with red hair, who also lack functional Mc1r genes. Male redheads had no problems blocking pain, presumably because they were using the NMDA circuit instead.

It’s early days, but if women do have a different pain-damping circuit to men, it could explain why there are sex differences in responses to opioid painkillers. Women get more relief from the opioid painkiller nalbuphine compared to morphine, whereas in men morphine is more effective and nalbuphine actually increases the pain intensity. The findings could eventually lead to new painkillers tailored to be more effective in women, but Mogil isn’t holding his breath. “For now there isn’t a big enough and uncontroversial enough literature in any of these differences to justify drug development of any single one of them,” he says.

Similar difficulties have blighted developments in mental health – another area where there are known to be sex differences. Women are diagnosed with depression twice as often as men, for example, and their brains typically produce about half as much serotonin – a neurotransmitter linked to depression. Earlier this year, Anna-Lena Nordström, from the Karolinska Institute in Stockholm, Sweden, found that healthy women have more of the most common type of serotonin receptor than men but fewer serotonin transporters, which are needed to recycle serotonin. It hasn’t been shown that variations of this set-up make some women more prone to depression, but Nordström points out that transporter differences between men and women are of particular interest because this is where antidepressants like Prozac act, and because there is evidence that women respond better to such drugs than antidepressants that act on neurotransmitters other than serotonin.

Males may be less likely to suffer depression, but that doesn’t mean they get an easy ride. Boys are more likely to be diagnosed with autism, Tourette’s syndrome, dyslexia, stuttering, attention-deficit disorder and early-onset schizophrenia. Margaret McCarthy of the University of Maryland in Baltimore believes that hormone-like substances called prostaglandins, which help masculinise the male brain shortly before or after birth may be at least partly to blame. Prostaglandins are also known to cause inflammation, so McCarthy is investigating whether their action, if altered by infection or certain drugs, could cause inflammation and damage to the developing brain.

The ways in which men and women abuse drugs is another area that could reveal brain differences. While men are almost twice as likely as women to use cocaine, possibly due to social factors, when women take it they get addicted more quickly and have a more severe habit when they seek treatment.

Jane Taylor from Yale University suggested in 2007 that genetic differences may help to explain why. She compared mice that were engineered to either be genetically male with testes, genetically male with ovaries, genetically female with testes or genetically female with ovaries. She found that genetically female mice formed drug habits more quickly than the genetically male mice, regardless of which gonads they carried (Nature Neuroscience, vol 10, p 1398).

Jill Becker at the University of Michigan, Ann Arbor, has found something similar. She trained rats to poke their noses into a hole to get a dose of cocaine and compared the cocaine intake of female rats which had had their ovaries removed with castrated male rats. The females were bigger bingers. But when these females were given oestrogen, their total intake nearly tripled. That means that a genetic vulnerablility plus circulating sex hormones can add up to a crippling addiction.

Several studies have since found that women report that cocaine has a bigger positive effect when their oestrogen levels are high and their progesterone levels low. Suzette Evans at the Columbia University College of Physicians and Surgeons in New York City is running a clinical trial to test whether cocaine-dependent women can be treated by increasing their progesterone levels.

There’s much left to learn, but as the evidence mounts for sex-related influences on brain structure and function, the development of medicines better suited to a woman’s biology may yet take off. Before that can occur, however, more work is needed to uncover the differences between the brains of male and female animals. Despite recent progress, such work is very much in the minority.

Mogil, who has demonstrated big differences in pain processing in males and females, is astonished that so many researchers have failed to include female animals in their studies, especially when it comes to pain research. “It’s scandalous,” he says. “Women are the most common pain sufferers, and yet our model for basic pain research is the male rat.” On the flip side, it’s also an area ripe for exploration: “Every year or two we write a paper that says that something someone reported earlier is actually only true in males. We keep making people look bad. They are missing stuff completely.”


Myths and misconceptions


Give a man a sheet of paper printed with tangled streets and he can tell you where you need to go. But don’t be afraid to ask a woman for directions. Chances are she’ll get you there, too, but using a different technique. Drawing on her hippocampus, she’ll offer you physical cues like the bakery, the post office and the Chinese restaurant.


He might not remember the details of the big blow-up you had during your honeymoon, ladies, but just because you can it doesn’t mean he’s insensitive. Women are simply better at remembering the details surrounding emotional events, because their amygdala is tuned to capture them.


Modern folklore claims women speak nearly three times as many words as men. Don’t believe the hype. Women and men both say 16,000 words a day, on average.


While it’s true that males mainly secrete testosterone from the testes, oestrogen is important to male brain development in the womb. In the male brain, testosterone is converted into oestradiol, which acts on oestrogen receptors and sets the hypothalamus to “male”. Brains apart: The real difference between the sexes, 16 July 2008, New Scientist


Written by alienrobotgirl

15 August, 2008 at 9:35 pm

Posted in The Science of FCI

7 Responses

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  1. I just wanted to say, very interesting blog! Been reading it a few weeks now. I love your scientific spirit, we share in common an interest in learning how common chemicals/vitamins/hormones interact in our body and brain.

    I find it interesting that estrogen reduces pain tolerance. I was aware women are more pain sensitive than men but I believed this might be more of an issue of testosterone having some kind of pain blocking-modifying effect.

    I was amenorrhetic (low estrogen) for four years, until recently… I’m learning all about how hormones affect my body lol. One thing I’m discovering is that I *LOVE* estrogen. It makes me manic, and when I’m manic, my pain tolerance is sky high… so for me, it actually works the opposite (estrogen->mania->cracked out pain tolerance). The few days before ovulation, I feel AWESOME and am not as sensitive to the aches and pains. However, estrogen does make me really intolerant of strong smells and sometimes it feels like my senses are magnified 10xs, especially smell and sound. I also totally lose my appetite (which I am not going to complain about, ha).
    Even though I get very manic, my ability to fall asleep is the best when estrogen is the highest. Paradox! I do tend to lose out on sleep because of the mania, though.
    I also have a freakish ability to actually tolerate glucose and metabolize it for energy like a normal human when estrogen is peaked (I eat a very low carb diet because I don’t use glucose normally).

    When my estrogen is low, I’m much more depressive and hypersensitive to pain; my whole body can ache at those times, secondary to the depression. I’m also hungrier and sleep worse and my blood sugar stability is absolute trash.

    On the other hand, too much progesterone acts like a vicious tranquilizer-mood stabilizer. It stops me from going manic (or too depressed for that matter) …but I much prefer the manic high of estrogen dominance. With progesterone dominance it’s like I’m in a daze, half asleep at any given time. Ironically, I don’t even sleep well with high progesterone, I develop bad insomnia (even though I”m very tired and lethargic, I just kind of lay around, in a daze, no real rest). I assume the increased stress hormones from progesterone are the reason for the insomnia (I”m very vulnerable to insomnia under stress hormone increase).
    I am completely lethargic and want to stay in bed. Not to mention it makes me a horrible food beast, gives me acne, and suppresses my immune system (which probably contributes to the acne, as well as vulnerability to feeling sick).

    In summary, give me estrogen plz… progesterone, avoid at all costs! TERRIBLE!

    Perhaps I’m different because I’m bipolarish?


    26 August, 2008 at 12:33 am

  2. Hi itsthewooo

    What you’re describing is very common in bipolar/cyclothymia women. Oestrogen affects dopamine levels. Bipolar women are also prone to irregular cycles and hormonal problems.

    I think a number of the negative symptoms you attribute to progesterone are actually caused by oestrogen withdrawal, which causes an endorphin crash and carbohydrate cravings.

    I suspect that there is more to the issue of pain perception than just male/female hormones. I too have a higher pain tolerance when I am in a hypomanic/high state.

    I do disagree on one point though. This is a point I have been trying to get across to a female relative who is going to have to get medicated for bipolar disorder because it’s becoming so severe (sadly, she can’t stick to ketogenic/failsafe, which I keep trying to explain has fixed the problem for me).

    Mania is not good. Mania and depression are two halves of the same problem. The opposite of mania/depression is calmness. It’s calmness you should be aiming for. I know mania feels great when you’re experiencing it, but it can cause you to do rash, dangerous, and impulsive things. People will notice there is something wrong with you and you may lose friendships over crazy behaviour. Mania can rapidly change into anger/irritability and back. Mania is just a sign that you’re unstable and you’re more likely to have a depressive crash in an unstable state than you are in a calm state.


    30 August, 2008 at 12:59 am

  3. I agree, some is related to low estrogen, but some are also related to high progesterone. Progesterone is what is responsible for the zombie-trance thing (unfortunately which I am experiencing now, grrr). Progesterone also kind of blocks estrogen, so it is true that high progesterone has a way of translating into relatively lower estrogen.

    I’ve come to recognize the estrogen withdrawal state too, in it’s purest form it can be experienced the 2 days after the LH surge. Depressed, lethargic, hungry, yet not sedated or hibernation-like (progesterone is what does the somewhat comforting hibernation/sedation painkiller dope up). The estrogen crash after ovulation is like having the floor pulled out under you. Estrogen crash feels much worse than progesterone dominance (although both feel pretty terrible) because the progesterone stabilizes and numbs the mind. Low estrogen is distinct and hard depression whereas at least with progesterone you’ve your doped up apathy and contentment.

    I suspect my estrogen is probably too low so that is causing some of the issues with progesterone; I take st johns wort for depression (though I have mood cycling the primary problem is depressive mood) I’ve come to learn that SJW has a way of lowering estrogen levels. I had the worst symptoms of progesterone dominance when taking 3 tabs/day, when I went down to 2/day things improved dramatically. I am too afraid to stop taking it because it has helped elevate my baseline mood. I suspect if I stopped taking it I would no longer have issues with progesterone dominance (who knows, maybe I wouldn’t need SJW anymore if I raised my baseline estrogen enough? Too afraid to try, though.)

    I hear you on the mood cycling, and I can totally relate to your cautions. When I feel “calm happiness” I am shocked, it happens so rarely, I have come to believe it is a choice between some degree of misery *or* a thrilled, agitated, pressured, wired sort of happiness.
    I just, find it really hard to be “worried” about hypomania, you know? I look at hypomania as my reward for a lifetime of depression, like the way a worker looks foward to the weekend off. It might be different if I were at risk for prolonged psychotic mania but I don’t see that happening. Since my primary issue is with depressive inhibition, even in my hypomanic states I am no worse than a nerd who got a alcohol buzz going, lol (that is to say, my symptoms are mild even if inside I feel radically different : I laugh louder, talk louder and faster, the worst thing I might do is buy stupid crap and start a fight with family or yell at strangers who are annoying and rude).
    Sometimes I have super crazy episodes where I run down the street dancing and I feel *completely* out of control of the energy. Sometimes the energy is so intense, it’s like I’m electrical wires, passive before it, like a conduit for spirits or something. At those times when I am just pouring energy uncontrolled, I do appreciate that hypomania is no better than depression. When the energy is preventing me from even concentrating ont eh smallest task, because my mind is flipping from thing to thing… yea, it’s no better than depression at those times.
    Then there are the bitter mixed states that bring what shall be called “psychotic like experiences” (distance from the world, confusion, paranoia, disorientation, imaging things that can’t realistically happen). Oh *god* I hate the mixed states, I always feel I might lose my mind when that happens.

    Anyway… I just don’t see another way, you know? I’m totally afraid of medicine (although, I recently heard about “lamictal” and it sounds like absolute god send for someone like me). I find it hard to justify medicine because my symptoms are “mild” and the side effects of bipolar medicine are considerable… if I think progesterone is bad because of the sedation and hunger how the hell can I tolerate a medicine that basically *replicates* what progesterone does to the brain (as in, turning it off, shutting it down, slowing and sedating it). I’m also afraid of depression getting out of hand, since the primary problem has always been depression and not mania.

    The ketogenic diet did *wonders* for my mood, though. When I was a fat fatty, I was very emotionally unstable, severely depressed (at the time I never would have thought I had mood cycling… the idea of me having hypomanic symptoms and energy was laughable to me). Within days of starting the ketogenic diet my mood became much more smooth and balanced, and my emotions became brighter. I thought I was cured of depression.
    I still eat very low carb, but no longer ketogenic. Sometimes I wonder if I go back to very strict carb restriction to deep ketosis levels (as was the case when I was rapidly losing weight) …maybe it would cure me again? I probably wouldn’t have the discipline to keep that up for life, though, especially when my depression/moods are “manageable enough” on a 60ish carb diet like this.


    2 September, 2008 at 9:35 am

  4. Hi Woo,

    If you have/might have bipolar it’s possible your hormones are normal but what is going on in your brain is an exaggerated reaction to the hormones, what with oestrogen affecting endorphin levels etc.

    I’m pretty worried about hypomania. Have you heard of the concept of ‘kindling’? Bipolar is in a sense like epilepsy. Basically, the more ups-and-downs you have, the stronger the malfunctioning parts of your brain become, and the more likely you are to have a major crash or a major manic episode where you might do yourself or others harm. In terms of your brain circuitry, mania and depresssion are equally as bad.

    ‘Sometimes I have super crazy episodes…’ That doesn’t sound like hypomania to me, that sounds like you’re on the verge of being manic.

    Ideally someone who is bipolar needs to be on a diet like me – a combination of a ketogenic diet and a failsafe diet. The failsafe part is very important. I am no longer able to maintain a stable mood and remain symptom-free on a low-carb diet alone. You need to cut out the amines and glutamates (neurotransmitters) and salicylates (which affect neurotransmitters) in your diet too. This WILL fix your depression, I promise you.

    Like you, I detest taking pills because I almost always get horrible side effects. I live with the possibility that I will need medicating some day, like a close relative of mine whose condition has recently become serious. Sometimes diet alone can’t fix things because it’s become too out of control, just as in epilepsy.


    24 September, 2008 at 1:00 pm

  5. Thank you so much for your reply to my long post.

    I think you’re right… my brain doesn’t respond right because of the mood issue.

    I have not had a period or a real cycle since august, and the hypomanic side of the coin has gotten heaps better since then. I think the summer, combined with reproductive cycles, it was making me *really* crazy and producing verge-of-mania episodes… I am hopeful that in the fall I won’t worry about the extreme manic/psychotic issues that were trouble in the summer. I discovered through research that warm weather makes dopamine receptors more sensitive… this would explain so much.

    As for the loss of the cycle, I don’t know what’s up with that. I think lack of ovulation in august might have been related to decreasing and stopping the st johns wort. In my first post I said I wondered what would happen mood wise/hormone wise if I stopped? I did experiment and taper down and eventually stop over a month’s time. I have come to the conclusion that I think the SJW actually was helping me to ovulate via increased dopamine/serotonin. I eventually did go back on the SJW because my mood slowly was dragging down into miserable depression. I caved in when I found myself crying and thinking about suicide again, never want to go back to that bad. It wasn’t reactionary to previous hypomania, this depression was pure depression. I also was getting hypoglycemia and ravenous hunger which I think might be related to neurotransmitter deficiency from lack of SJW.
    Stopping the SJW didn’t really affect my hypomania either way. THe only difference was I was no longer capable of euphoric hypomania and instead I had miserable, miserable mixed states. Mania did not get better until it started getting consistently cold.

    When I started the SJW again, my mood gradually picked back up, and I also felt like I might “ovulate” soon because I had a lot of those signs. I had very mild hypomanic symptoms, especially after staying up too late (sleep loss = mania) but nothing extreme like in the summer.

    I am very curious about the failsafe eating. I don’t consider myself reactive to food and mostly I just have a carbohydrate problem, but who knows, maybe it will help? I have noticed that foods high in glutamates like tomato sauce really make me hypoglycemic and very chaotic/depressive. I try to avoid tomato sauce as much as possible, it’s definitely bad mojo. I also notice gluten makes me feel numb and apathetic and a little depressive, and I also feel I’m making a lot of mucous after gluten, but only if I eat a lot of it. I also find whenever I eat chicken I can get quite ravenous, but I think that is because chicken produces more insulin than other meats (which I found in a study).
    I wish I knew more about foods, symptoms of intolerance, common allergens etc. Do you recommend any websites where I can start learning?


    24 September, 2008 at 9:06 pm

  6. Hi Woo

    So many women I know with bipolar tendencies also have menstrual problems and irregular cycles. There seems to be little info as to *why* online, but I know it’s a noted feature of bipolar. I think it has to do with dopamine fluctuation, as high dopamine causes low prolactin and vice versa. Prolactin can give you irregular periods or even stop them altogether. Prolactin also messes with your sex drive. I’m going to make some posts on bipolar soon that might make the connections all a bit clearer.

    Re: failsafe eating. Most people never spot a connection to food before they begin the trial elimination diet. Food chemicals are quite ubiquitous, so it’s very hard to spot a connection. Virtually everyone I know who has been helped by the diet has said they have a problem with carbohydrate/hypoglycaemia etc. There are a number of mechanisms for this. Salicylates, amines, and glutamates all stimulate excess insulin release. The reason chicken produces more insulin than other meats is because the skin is very rich in amines, and sometimes it has been injected or brined in flavour enhancers (glutamates). Skinless chicken is fine.

    If you visit my main website, and also the Food Intolerance Network,, these sites will give you all the info you need about the symptoms people get and how to perform the diet.


    25 September, 2008 at 9:24 pm

  7. Oh yeah,

    > I discovered through research that warm weather makes dopamine receptors more sensitive…

    Very interesting. Failsafers tend to feel better during the summer and worse during the winter… and in some cases more manic during the summer and more depressive during the winter.

    In bipolar, there’s quite a lot of evidence that dopamine highs and lows (rather than serotonin) dicatate the happy/sad states.


    25 September, 2008 at 9:54 pm

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