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HPA axis

Hypocretin Neurons: The Link Between Fasting, Stress, and Arousal, or, Why Fasting Breeds Insomniacs

Posted by on Apr 30, 2012 in Blog, Fasting, HPA axis, Neurobiology of Eating, Sleep | 16 comments

Hypocretin Neurons: The Link Between Fasting, Stress, and Arousal, or, Why Fasting Breeds Insomniacs

There is a hell of a dichotomy occurring in the Paleo blogosphere this month.   99 percent of the time I am pleased as Pooh stuck up a honey tree, nestled in my esoteric corner of paleo-feminist rage, but every once in a while I wish more people could hear what I have to say.  Today is one of those days.

The split I am talking about is not all that nefarious.  In most cases, it’s benign and can be ignored.   But in general I would like to draw attention to it, because I think there’s a lot going on beneath the surface (and here, the depths are not just Nemo and Dory but are instead people’s lives), and that depth requires speaking to.  Immediately.

Mark’s Daily Apple has recently done a beautiful series on the benefits of fasting.   I loved it.  I learned plenty, as I always do on MDA.  The series was well-written and -organized, and in fact I ended up directing people who are unfamiliar with fasting to the site in hopes of swaying their opinions.   (So let it be clear: I am not against fasting per se.) Yet Chris Kresser has also done an April “Best your Stress” challenge.   Serendipitously enough, it concludes today.  And it is exactly what it sounds like: an endeavor to spend 30 days taking practical steps to counteract stress.  Chris’s idea was that people often spend 30 days trying to get their diets in line.  But what about their stress, and their lives?  I couldn’t agree more.   This man is a gale of fresh, important ideas.

The reason I say these two Big Themes are at odds is because they are.  Fasting is a stressor.  Period.  Mark Sisson would agree.  All people who advocate fasting would agree.  But all they ever do is put an asterisk at the end of their posts: *people who are stressed should probably not fast, they say.   But why?  Who is affected, and how?   What can fasting and other forms of restriction do to our brains, and to our lives?

What I want to draw attention to today are little loci that sit on the border of the hypothalamus called Hypocretin Neurons.    Hypocretin neurons (also called Orexins–and note that the word “orexin” means “appetite increasing”) were discovered just 14 years ago in 1998, but they have radically altered the landscape of eating neurobiology since then.   No, they are not the sole molecules responsible for sleep and waking.  Mice that have had these neurons removed still sleep and wake in roughly normal patterns.  But they never feel alert, and they never suffer insomnia.  And when the neurons are activated, the mice leap into action.  Hypocretin neurons wake animals up.  This much is certain.

The lack of Hypocretin Neuron signalling is the cause of narcolepsy, while elevated Hypocretin levels induce arousal, elevate food intake, and elevate adiposity.  Hypocretin Neurons  upregulate the production of molecules down several other pathways, too: these include noradrenergic, histaminergic, cholinergic, dopamine, and serotonergic.

The anatomy of Hypocretin Neurons is also coming into greater light.   When are the neurons active?  What signals do they receive, and what signals do they produce?     Research is beginning to show that Hypocretin Neurons are excited by excitatory synaptic currents and asymmetric synapses with minimum inhibitory input.   The fact of asymmetry is important.  It means that Hypocretin Neurons are instead always acted upon by mostly uniform – excitatory - signals they receive.    Hypocretin Neurons only ever up-regulate and relax.  They do not down-regulate.   Excitatory signals outnumber inhibitory signals 10:1.

One notable source of excitation is corticotrophin releasing hormone, which suggests that stress activates the activity of Hypocretin Neurons.    GABA neurons also create a bridge between Neuropeptite Y, which is the molecule that arguably has the strongest appetite-stimulating effect on the brain, and Hypocretin Neurons (more on Neuropeptide Y later this week).  From there, Hypocretin Neurons project to all regions of the brain, including the hypothalamus, cerebral cortex, brain stem, and spinal cord.   It seems as though Hypocretin Neurons may act as a nexus of signal input for the appropriate synchronization of various autonomic, endocrine, and metabolic processes.

Food restriction further augments recruitment of excitatory inputs onto Hypocretin cells.   This explains the relationship between insomnia and adiposity: because of the easy excitability of Hypocretin Neurons, any signal that triggers their activity, regardless of homeostatic needs, will elevate the need to feed in brain circuits such as the locus coeruleus and the melanocortin system while also promoting wakefulness through activation of noradrenaline-stimulating neurons.  Anything that promotes the release of corticotrophin releasing hormone (CRH) such as reduced sleep will further trigger Hyocretin Neuron firing and Appetite.   This is a vicious cycle.  Hypocretin Neurons play the role both of trigger and of accelerator, taking states of wakefulness, insomnia, stress, and obesity into continual positive feedback loops.

So how does leptin factor in?  Hypocretin Neurons express leptin receptors.   Moreover, some recent complicated neurobiological work done on mice has shown that injecting them with leptin decreases the activity of their Hypocretin Neurons.   What this means is that Hypocretin Neuron activity is stimulated in part by decreasing levels of leptin in the blood, and that increased leptin levels reduce the level of excitation running through Hypocretin Neurons.   This is coupled by ghrelin activity, which is also detected by Hypocretin Neurons.   Ghrelin, which originates in the gut and is known to stimulate appetite, also excites Hypocretin Neurons.   What does feeding do, then, for Hypocretin Neuron excitation?   Experiments on mice show that re-feeding restores normal Hypocretin activity, to an extent.  Repeated abuse takes longer to recover from, but the simple presence of leptin in the blood normalizes the brains of mice.

Hooray!  This is good for fasting, right?  So long as one re-feeds appropriately, everything should be fine?  Well, yes.  In a healthfully functioning individual.  But not in a) someone who is both stressed and leptin resistant, since increased leptin levels from the re-feed might not be powerful enough to offset other excitatory pathways b) someone who is currently emerging from yo-yo dieting or caloric restriction c) someone who is dealing with an over-stimulated appetite, d) someone experiencing stress, e) someone who has had a history of insomnia, f) someone who is underweight, since they have low leptin levels, g) anyone who has ever had an eating disorder, particularly bulimia or binge eating disorder or h) anyone with HPA axis or endocrine dysregulation, particularly women, including overt stress, hypogonadism, hypothalamic amenorrhea, hypercortisolism, or hypocortisolism (adrenal fatigue.)  I am sure the list is incomplete.

In animals, Hypocretin Neurons serve an important evolutionary function.  Arousal is a vital behavior in all species.    And normally, Hypocretin Neurons respond quickly to changes in input.  But in situations of chronic metabolic or endocrine stress, or of recovering from a stressor, they can lead to hyper-activity and hyper-feeding.

Researchers have long known about the link between leptin, sleep, and obesity.  The less someone sleeps, the lower her leptin levels, so the more she eats, and the heavier she gets.  Hypocretin Neurons may serve as one of the answers to the question of exactly how that phenomenon comes about.  Or at least it plays a role.  Because 1) Hypocretins simultaneously stimulate appetite and wakefulness, particularly through orexigenic output of the melanocortin system, and subsequent release of CRH, which activates the stress response, and 2) while Hypocretin Neurons wake us up, they also need to be quiet enough for people to go to sleep.

Finally, I raise the questions: how many disordered eaters have trouble sleeping?  How many anorexics, binge eaters, calorie restrictors, exercise-addicts, stressed-out individuals, and very low-carb dieters have trouble sleeping?   How many people try intermittent fasting and find that it disrupts their sleep or circadian rhythms?  How many people wake up in the middle of the night or early in the morning, even though they still need sleep, but for the life of them feel so awake?  Part of that answer lies in blood sugar metabolism, for sure.  And in other places.  Sleep is a hell of a complex phenomenon.  But here– Hypocretin Neurons can become overburdened by excitatory signals.  They get hyped up in the face of both decreasing leptin levels and leptin insensitivity.   They are upset by restriction, and they are upset by fasting.  Hypocretin Neurons demonstrate why so many people have difficulty with their appetite and their sleep.  If you find that fasting disturbs your sleep, or that you are suffering disordered circadian rhythms along with stress or appetite problems, do you best to relax your system.  Don’t fast.  Relax.  Exercise less.  Reduce stress.  Eat more.  Put on weight.  Eat more carbohydrates.  Don’t graze.  Increase your leptin sensitivity.  And listen to your body.

Coming up next: nighttime eating syndrome, and how it’s all related.



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Leptin, Sleep, and Obesity: Is Reduced Sleep Making America Fat?

Posted by on Apr 30, 2012 in Blog, HPA axis, Neurobiology of Eating, Sleep | 0 comments

Leptin, Sleep, and Obesity: Is Reduced Sleep Making America Fat?

The literature on sleep and obesity is becoming dense.  Lots of things happen to people when they sleep.   One of them has to do with appetite regulation, so many researchers are coming to believe that sleep plays a dominant role in today’s vast American Overfeed.

This hunch is supported by striking correlations.

In 1960, a survey of over 1 million people found a modal sleep duration of 8-9 hours. In 2002, polls conducted by the National Sleep Foundation indicated that the average duration of sleep for Americans had fallen to 6.9-7 hours.  Recent data indicate that a higher percentage of adult Americans report sleeping 6 hours or less. In 2005, in the US, more than 30% of adult men and women between the ages of 30 and 64 years reported sleeping on average less than 6 hours each night.   This decrease in sleep duration has occurred over the same time as the increase in the prevalence of obesity and diabetes.

Leptin has a distinct diurnal and circadian rhythm.  It has minimum values during daytime and a nocturnal rise with maximum values during early to mid sleep.  The amplitude of the circadian variation averages approximately thirty per cent.    Leptin levels rise during the night to suppress appetite while sleeping.   Moreover, the reduction of leptin at night spells bad news for the rest of the day: it sets the individual up not just with lower leptin levels in general but also decreased glucose tolerance and an increased craving for carbohydrates.

In order to test the effects of sleep deprivation on leptin production, a number of studies have been conducted.  They’re all fascinating, so I have provided a quick review of some of the more revealing studies.

1)   Many studies are conducted on people with sleep apnea.   Epidemiological studies show that they are heavier than the rest of the population.  They have greater rates of diabetes and metabolic syndrome.  Yet when their sleep apnea is corrected, these people lose weight naturally, and their metabolisms normalize.  This probably has to do both with decreased appetite as well as improved metabolic functioning.

2) In one study at the University of Chicago, doctors measured levels of leptin and ghrelin in 12 healthy men. They also noted their hunger and appetite levels. Soon after, the men were subjected to two days of sleep deprivation followed by two days of extended sleep. During this time doctors continued to monitor hormone levels, appetite, and activity.  The end result: When sleep was restricted, leptin levels went down and ghrelin levels went up. Not surprisingly, the men’s appetite also increased proportionally. Their desire for high carbohydrate, calorie-dense foods increased by a whopping 45%.

3) In another study at the University of Chicago, a similar protocol was conducted but men were asked to return a year later for a comparison. For six days they got four hours of sleep — their week of sleep deprivation.  The men’s food and activity levels were strictly regulated and hormone levels were taken during the day and while they slept.   One year later, the men returned for a six-day study with an 8-hour sleep period, so they served as their own comparison group.  The results: After their six-day sleep deprivation period, volunteers had a leptin decrease ranging from 19-26 percent.

4) In another study — a joint project between Stanford and the University of Wisconsin — about 1,000 volunteers reported the number of hours they slept each night. Doctors then measured their levels of ghrelin and leptin, as well as adiponectin, insulin, glucose, a lipid profile, and they also charted their weight.  The result: Those who slept less than eight hours a night not only had lower levels of leptin and higher levels of ghrelin, but they also had a higher level of body fat. What’s more, that level of body fat seemed to correlate with their sleep patterns. Specifically, those who slept the fewest hours per night weighed the most.

5)   In the final study, young, healthy subjects who were studied after 6 days of sleep restriction where they were allowed four hours in bed. After full sleep recovery, their levels of blood glucose after breakfast were higher in the state of sleep debt despite normal or even slightly elevated insulin responses. The difference in peak glucose levels in response to breakfast averaged was large enough to suggest a clinically significant impairment of glucose tolerance. These findings were confirmed by the results of intravenous glucose tolerance testing. Indeed, the rate of disappearance of glucose post injection was nearly 40 per cent slower in the sleep-debt condition than after recovery, and the acute insulin response to glucose was reduced by 30 per cent.

How fast do leptin levels recover from sleep deprivation?

Leptin levels recover almost as soon as regular sleep is resumed, at least in controlled studies.  In the first night.  However, these studies occur over a week or two at most.  If the sleep deprivation is chronic, it seems to have the same effect as fasting does on leptin.  Levels remain low–at least for some time–despite resumption of “normal” sleep or eating.  It takes time for the system to re-equilibrate after chronic stressors.

How does stress act on this system?

Stress activates cortisol secretion, but it also stimulates sympathetic nervous system activity.  This gets adrenaline running in the system, increases heart rate, and increases blood pressure.  These two things increase during both partial and acute sleep deprivation.  It is well kown that andrenergic (adrenal-related) receptor activation is suppressive of leptin production, and that leptin is reduced in response to adrenaline infusions.  For this reason, whatever dampening that stress puts on sleep negatively affects appetite activity.

There are other downstream effects of sleep deprivation.   I’ll cover some of them briefly here, then hopefully return to them each on their own.

1)  More cortisol dysregulation.  One effect of sleep deprivation is a decrease early evening cortisol levels.   Normally at that time of day, cortisol concentrations are rapidly decreasing in order to attain minimal levels shortly before habitual bedtime.  Yet in one study the rate of decrease of cortisol concentrations in the early evening was approximately 6-fold slower in subjects who had undergone 6 days of sleep restriction than in subjects who were fully rested. This means, basically, that it takes longer for people who have lost sleep to ramp down from that stress and be able to go to sleep again.

2)  Thyroid reduction.  In one study, after 6 days of 4-hour sleep time, people experienced a striking decrease in the normal nocturnal TSH rise, and the overall mean TSH levels were reduced by more than 30%. A normal pattern of TSH release reappeared when the subjects had fully recovered. T4 was higher in the sleep-restricted condition than the normal condition, indicating that decreased sleep decreases the body’s rate of conversion from T4 to T3.

3)  Growth hormone reduction.  The temporal organization of Growth Hormone secretion is also altered by chronic partial sleep loss. The normal single GH pulse occurring shortly after people fall asleep splits into 2 smaller pulses, 1 before sleep and 1 after sleep.  With decreased sleep, peripheral tissues are exposed to high GH levels for an extended period of time.  GH has anti-insulin-like effects, so an increased overnight exposure to GH negatively impacts insulin sensitivity and glucose tolerance.



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The HPA axis: Psychological Stress and Hypothalamic Amenorrhea

Posted by on Apr 27, 2012 in Blog, HPA axis, Hypothalamic Amenorrhea | 14 comments

The HPA axis: Psychological Stress and Hypothalamic Amenorrhea

I’m going to pick up here where I left off on my last post.  There, I covered the role that exercise and energy deficits play in HPA-axis-induced amenorrhea.  Here, I cover the effects of psychosocial stress, and also how the two kinds of stress play off of each other.

Hypothalamic amenorrhea (HA) typically results from pschyogenic stress coupled with a mild energy imbalance– so generally both social stress and metabolic distress are present.  These two stressors are too intertwined to separate out in studies. Hypothalamic Amenorrhea affects 5 percent of women of reproductive age, and subclinical women I suspect double that number, at least.

It is generally believed that psychosocial dilemmas activate neural pathways (ie, worrying about a job will stem from the prefrontal cortex) and hit the HPA axis that way, whereas exercise and weight loss disturb the HPA axis via metabolic disturbance.  Although it seems logical that specific cascades exist for different types of stress, there is currently no method for clearly delineating psychogenic from metabolic stress.  Psychogenic stress almost always has metabolic costs as well.  These stem from perfectionism and body image issues, and they include stressors such as food restriction and excessive exercise.  For this reason, it’s impossible, almost actually impossible, to study the two sources of HPA axis stress independently.


One way to test the potence of pyschosocial stress on female fertility is with primate studies.  They parallel humans closely.   This is nice.  It enables researchers to control for all of the variables that affect human lives.

This is how big of a deal it is:

In one study, across more than 1200 menstrual cycles in cynomolgus monkeys, the stressed out, socially subordinate monkeys consistently exhibited ovarian impairment, whereas others did not.  The thing is, in primate societies, much as in our own, it is inherently stressful to be at the bottom of the social ladder.  All that researchers have to do in order to study primate fertility is to monitor the behaviors and physiology of lower rung versus higher run monkeys.  For the lower rung monkeys in this study, their cycles increased in length and variability, and both their levels of progesterone and estradiol dropped.  Additionally, they experienced elevated cortisol levels (almost in a perfect inverse relationship with the estradiol), as well as osteopenia, which is the precursor to osteoporosis.   The researchers also tested soy on the monkeys to see if it would help.  It did not.  These monkeys were not energetically stressed.  They ate the appropriate amount of food.  The only thing that had the power to change their reproductive capacity was psychosocial stress, and it made a significant impact.

The stressors associated with stress-induced amenorrhea are many.  They include affective disorders, eating disorders, various personality characteristics, drug use, and external and intrapsychic stresses.   “External and intrapsychic stresses” sounds clinical and like a small category of disease, but it is in fact huge.  If you think you are fat, if you think you are stupid, if you think you are ugly, if you think you aren’t good enough, if you think other people think you’re fat, stupid, ugly, or not good enough… the list goes on and on.   “Intrapsychic” stress is the nebulous stuff that women impose on themselves–encouraged by society or otherwise–and it kills their HPA axes.   Almost literally.   Cortisol blocks signalling to and activity of both the pituitary and thyroid glands, in addition to on hormones themselves while in isolation in the bloodstream.  Moreover, we all know that cortisol acts on other systems and tissues in detrimental ways.   The stress of living in today’s world is one of the greatest health threats a woman can face.

In one study, women with stress-induced hypogonadism were compared with a) “normal” women and b) women with hypothalamic hypogonadism from other pathologies.  Those with stress issues were the only ones who measured unrealistic expectations and dysfunctional attitudes.  They were both highly perfectionistic and sociotrophic, which is defined as (its amazing we even have a word for this)– a high need for social approval.   Perfectionism and sociotrophy play off of each other.  Perfectionism interferes with social approval, and social approval feeds back on notions of what being perfect is, such that women with stress-induced hypogonadism face an intrapsychic conflict that might be too difficult to resolve.   Additionally, being perfect is, well, an unrealistic expectation.  Unrealistic expectations are not, generally, good for the soul.

Women with stress-induced hypogonadism also test as having trouble realxing and having fun.  They do not typically meet the criteria for eating disorders, but they do as a whole exhibit disordered eating.   That’s almost as insidious, in my book.   And they do exercise a lot.  These two facts of disordered eating and excess exercise do not help the stressed out hypothalama.

Because other sources of hypothalamic stress, as we’ve covered, include caloric restriction, excess exercise, and low body fat, all of which signal to the hypothalamus that the body is starving.  These very often act in concert with psychosocial stress, a la the perfectionism discussed above, and feed off of each other in nasty ways.

For example, women become amenorrheic when suffering from anorexia.  Clearly this is a metabolic effect, but the self-tortured stress and the isolation that often accompany anorexia take huge tolls from the cognitive angle as well.  And tellingly: once anorexic women both regain weight and supplement with exogenous hormones, such that their systems should be working normally, they still often do not experience bone accretion.  Bone accretion is enabled by estrogen.  The fact that these women still lack estrogen demonstrates that the normalizations these women experience from regaining weight are not whole sale.  They are ineffective, and clearly not all parts of the HPA axis are working properly.  This is likely because psychological stress is still high and the adrenal glands have not yet recovered.  It may also be due to ongoing metabolic derangements such as altered growth hormone action, or hypothalamic hypothyroidism.    These women’s systems need time to recover.  But they also need psychological healing, or else the HPA axis will not run happily.

In one study, 88 percent of women with hypothalamic amenorrhea recovered menstruation with just 20 weeks of cognitive behavioral therapy.   Amazing!  Soon I will write a post on recovering from HA, and cognitive behavioral therapy will play a big part in it.  Additionally, I am currently studying cognitive therapy for women with eating disorders–which is unsurprisingly close to what I’ve been doing with women for years–so once I am learned-enough I will share and use all of that information that I can, too.

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The HPA axis: Metabolic Distress and Hypothalamic Amenorrhea

Posted by on Apr 24, 2012 in Blog, HPA axis, Hypothalamic Amenorrhea | 27 comments

The HPA axis: Metabolic Distress and Hypothalamic Amenorrhea

If it hasn’t been clear yet, the hypothalamic-pituitary-adrenal (HPA) axis is one of the leading contributors to poor reproductive health.  The pituitary gland tells the reproductive organs what to do, and the hypothalamus tells the pituitary gland what to do, and the adrenals produce cortisol which influences the activity of both the hypothalamus and the pituitary glands.  Yikes.

Hypothalamic amenorrhea– or the loss of menstruation via disturbance to the HPA axis–affects 5 percent of women of reproductive age.  Subclinical women I suspect double that number, at least.  Many problems emerge as a result of HPA axis dysregulation that do not go as far as HA.  If it does advance to that stage, recovery from HA requires the restoration of normal cortisol function, the normalization of glandular tissue, and also rectification of the hypothyroidism that usually follows from hypothalamic dysregulation.

The HPA axis is dysregulated by all types of stress.  Acute stress is handled fairly easily, as the HPA axis is typically stable and in fact built to optimize an individual’s response to stress.  But chronic stress is– as we are all well aware– half of one of Satan’s eyelashes away from downright insidious.

Yet chronic stressors are divided by themselves into even more particular categories: psychosocial stress on one hand, and metabolic distress on the other.  Psychosocial stress is caused by mental, emotional, and social factors.  Metabolic distress is caused by living in an energy deficit, which is in turn caused both by calorie restriction and excess exercise.  These two forms of stress affect the HPA axis via different mechanisms.  Yet it should be another obvious fact for you that psychosocial stress and metabolic distress almost always go hand in hand.

This post is going to focus on metabolic distress.  I’ll treat the psychosocial and how these two are interrelated in the following post.


I talked a bit in my previous posts about the HPA axis and how different pathologies can emerge from hyper-activity of the axis and hypo-activity.  Metabolic distress pushes the axis in hyper activity, at least for as long as the system can handle it before burning out.

The pathology of Hypothalamic Amenorrhea in general

The point of the HPA axis is to metabolically mobilize individuals in stressful circumstances.  So in them, stress levels rise.   In one study, the degree of ovarian compromise women suffered was in a precise inverse relationship with observed cortisol levels.   That’s pretty amazing.  What the cortisol does is perform negative feedback on the hypothalamus, such that the hypothalamus releases GnRH (gonadotropin releasing hormone) in decreased quantities.  Without GnRH, the pituitary doesn’t get the signal to more of its own hormones.  These include LH and FSH, hormones that in turn signal to the ovaries how much estrogen they should be producing according what time of the cycle it is.  The Pituitary is also responsible for secreting thyroid stimulating hormone (TSH).  Ordinarily, TSH levels rise or fall  in response to changes in T3 and T4 levels in the blood.   In HA, the pituitary never receives these signals, so TSH levels do not increase when they should.    This leads to the HPA axis setting an altered hypothalamic set point: it decreases as much as what is seen in hospitalized patients who develop what is called “sick euthyroid syndrome.”    Additionally, due to HA, the secretory patterns of growth hormone, prolactin, and melatonin vary.  This is problematic for a wide variety of reasons, not  the least of which are sleep, tissue repair, and hormone development.

Exercise, weight loss, and metabolic distress

When compared with normally menstruating but sedentary women, amenorrheic athletes demonstrate less progesterone secretion, fewer LH pulses from the pituitary in a day, and higher cortisol levels.  Amenorrheic athletes that are anovulatory have the fewest LH pulses in a day of all groups of women and the highest cortisol levlesl despite comparable leves of exertion and fitness among these athletes and others.  This is all to say that athletes experience greater risk of amenorrhea.

Though both sorts of stress are important for the ovaries, there is no doubt that exercise and weight loss serve as stressors all their own.  In monkeys trained to run, it has been shown that caloric supplementation reversed the anovulation induced by training.  Interestingly, the monkeys did not spontaneously develop a compensatory increase in appetite and had to be bribed with colorful candy to consume more calories.   The HPA axis was downregulating their drives to eat.    Studies in women also indicate that exercise and weight loss cause anovulation, probably through decreased GnRH release.  One team of researchers, Louks and Thurma, quantified the amount of energy restricted (absent of psychosocial stress*) needed to impact GnRH release in normally menstruating women.  They fed the women an energy stasis of 45kcal/kg of mean body mass per day.  This amounts to approximately 2200 calories for a woman weighing 110 pounds.  They administered graded daily energy deficits of 10, 25, or 35 kcal/kg.  This yields absolute values for the 110 pound woman of 1750 calories per day, 1000 calories per day, and then, Yikes!, 500 calories/day.  An energy deficit of 33 percent showed no impact in LH pulse frequency after 5 days, and an energy deficit of 75 percent showed a 40 percent decrease in LH in 5 days.  I imagine that both of these numbers would be more signficiant with longer time periods. Much more significant.   For all energy deficits cortisol levels rose.    At the 75 percent reduction, cortisol levels rose by 30 percent.  For the women who had the lowest progesterone levels at the start of the study, the cortisol levels and reductions in LH were impaced the most.  Most women, I’d imagine, who enter into such deficits do not have them imposed, but rather choose them.  This indicates to me that they are under a great deal of stress as well, such that the “stressed” women tested in this study probably closer approximate the majority of real American women.

*(On the other hand, modest dietary restriction accompanied by small amunts of exercise greatly increased the proportion of monkeys who become anovulatory when presented with social stress.   Social stress is also a significant factor in amenorrhea.)

The question remains: Is it the stress of exercise or the energy deficit that alters LH pulsatility in exercising women? This key question has been answered maybe by controlled studies in which women undergo dietary caloric restriction imposed in the face of increasing exercise demands. It would appear that LH pulsatility is not disrupted by the stress of exercise but rather by reduced energy availability.   With increased calories, the women don’t experience as much LH disturbance as when they don’t meet their caloric needs.  Presumably, then, sufficient calorie ingestion would really help mitigate the problem for women suffering exercise-induced HA.   According to this one spate of studies.   Honestly, I’m not sold.  Muscle tear down and growth, and any repair that occurs on joints and other tissues, involves the activation of inflammatory responses.  Cortisol rides along with those.  If the exercise and the resulting cortisol is significant enough, supplementation with calories cannot cure everything.  Additionally, the psychosocial stress that accompanies excess exercise plays a role.  Additionally, thyroid function may be negative impacted by trying to make up for fluctuating caloric intake.  And finally, I find it implausible that women outside of controlled studies will know precisely how much they need to add to their diets in order to achieve the proper balance.

Nutriton and metabolism play critical roles in all of this.    (Note: the few studies done on men in this realm suggest that undernutritional is as deleterious to reproductive competency in men as it is in women.)  Metabolic imbalance occurs when energy expenditure exceeds energy intake, right?  This is important for our bodies, so there are many different (and redundant) signals to the brain from metabolic systems.  This makes it hard to suss out what system does precisely what, and which is the most important in studying these issues.  Signals reflecting energy stores, recent nutritional information, and specific classes of nutrients are integrated in the central nervous sytem, particularly the hypothalamus, to coordinate energy intake and expenditure.    Chronic energy deficiency alters thyroidal function to slow metabolism and correct negative energy balance.

Putative appetite suppressing and satiety signals include cortisol, CRH, insulin, glucose, resistin, leptin, proopiomelanocortin POMC, cocain- and amphetamine-regulated transcript CART peptide, peptide YY, and glucagon=like peptide 1.  (Yikes!)  The hormones from fat cells implicated in energy regulation include leptin, adiponectin, and resistin.  Leptin, which we all know and love, is the dominant long-term energy signal informing the brain of fat reserves– it is also a satiety signal.  It’s a big deal, and for women’s with HPA axis dysregulation, having lots of it, or at least good sensitivity to it, is helpful.   Adiponectin acts as an insulin-sensitizing agent by reducing hepatic (liver) glucose production.  This one, contra leptin, is reduced in obesity.  Resistin is linked to insulin tolerance and decreases glucose uptake by fat cells.  Ghrelin is produced by the gastrointestinal tract.  Plasma ghrelin levels rise during fasting and immediately before anticipated mealtimes and then fall within an hour of food intake, suggesting that ghrelin is important for meal initiation.

Resistin levels correlate with free cortisol levels, indicating that in states of stress the body is trying to sensitize the body to insulin.  Adoponectin correlates with insulin sensitivity, too, particulalry in studies of depressed humans.    In women, ghrelin levels increase in both anorexia nervosa and exericise amenorrhea.  No surprise there.   The greater the energy deficit, the more the body wants to eat.

Leptin is crucial.  Importantly, women who primarily suffer from psychosocial stress and not metabolic distress recover from hypothalamic amenorrhea without changing weight or leptin levels.   What this tells us is that leptin is mostly a problem for women who suffer energy deficits.   Studies of rodents as well as of women indicate that increasing leptin and leptin sensitivity induces regularity.  When mice are injected with leptin during a fast, for example, their cycles remain the proper length.   Without leptin, however, their cycles become longer and irregular.

Leptin is produced by fat cells.  Some other tissue produces it as well, but not as significantly.  Low body fat is a very significant problem for hypothalamic amenorrhea.   This is indicated by the fact that while many athletic women experience HA, women who participate in sports that require thinner physiques have much greater rates of HA.
Depending on the type of sport and competition level, the incidence of amenorrhea varies from 5 to 25%.   The rates of HA in sports that require low body weight are as high as 6-43 percent in ballet and 24-26 percent in long distance running. In less stringent sports, such ad bicycling and swimming, the rates of HA are both 12 percent.  All that is to say that low body fat is a clear signal that the body is running in an energy deficit.  When this is the case–that is, when the body is running at a deficit– it thinks its starving.  No, I’m sorry, it doesn’t think it’s starving.  It is starving.  So all of the satiation hormones– in this case ghrelin, resistin, and leptin– they muster their collective powers and try to get the body to eat more.    If that does not happen, and if leptin levels are too low, the hypothalamus will not receive the signal to start the reproductive hormone cascade.


All that said, the factors that cause, respond to and mitigate metabolically induced hypothalamic amenorrhea are many and complex.   In the end, they can almost be reduced to a leptin problem.  But leptin is an issue solely because of low body fat and energy deficits (*as well as any leptin insensitivity, which I will treat in another post).   There are also the issues of inflammation and stress that arises from exercise, as well as psychosocial stress–all of which build upon each other in the complex interactions between the HPA axis and the body at large.

In the following post, I’ll deal with psychosocial stress, and how these two are related.  Afterwards I will deal with recovering from hypothalamic amenorrhea.



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HPA axis: what is pregnenolone steal?

Posted by on Apr 23, 2012 in Blog, HPA axis | 4 comments

HPA axis: what is pregnenolone steal?

The human response to a stressful situation occurs in two places.  First, it occurs immediately in the sympathetic nervous system.  This increases heart rate, increases breathing rate, initiates sweating, dilates pupils, jacks up blood sugar, and inhibits peristalsis.  Among other things.

Secondly, this amped up signal is relayed to the endocrine system via the hypothalamus.     Immediately, the HPA axis gets adrenaline pumping out of the adrenal glands.  Secondarily, via CRH secretion to the pituitary, and ACTH secretion to the adrenals, cortisol is secreted into the bloodstream.  The secretion of cortisol is a fast action, but it is a bit slower than the first-up, lightning-fast reaction of the nervous system I described above.  It also endures for longer.  This is true especially if the stress doesn’t run it’s course quickly, for example, if you hate your job.  Cortisol has many of the same physiological effects as activating the sympathetic nervous system does, at least on the surface.  It spikes blood sugar, inhibits digestion, and, importantly, puts a halt to immune activities.

So how does the body so easily produce enough cortisol to flood the system like this in times of need?

It steals it!   It “steals” the common building block of adrenal hormones, pregnenolone, from it’s ordinary functions.  It diverts production down a specific cascade that leads to cortisol.  This enables lots of cortisol production, but it inhibits the production of just about everything else.

Cholesterol is the mother molecule of the endocrine system.   Mitochondria, controlled by the adrenals, convert cholesterol into pregnenolone.  From pregnenolone, virtually all of the rest of the hormones are produced.   From here, one of two things can happen:  the pregnenolone can be converted to progesterone or it can be converted to DHEA.  DHEA is the precurosor to all of the other sex hormones, at least those produced by the adrenal system.


This means that a stressful situation will steal all of the pregnenolone from its normal production of DHEA and shunt it into cortisol.   The body will prefer this pathway to the detriment of all other adrenal pathways.   Hormone production will suffer greatly.

You might object to how detrimental I’m making this sound because you understand that most of the sex hormones are produced in gonadal tissue.  This is correct.  However, there are a handful of complicating factors that make what could have been the reproductive system’s saving grace ultimately problematic.

First: non-dominant sex hormones (such as testosterone in a woman or estrogen in a man) are often produced in the adrenal glands at higher levels than in the gonads.  For example, the largest source of testosterone in the female body is the adrenal gland, even though a woman does produce small amounts of testosterone in her ovaries.   Secondly, the production of sex hormones in the adrenals is still important for the overall level of sex hormones in the body, particularly for achieving hormonal balance.  The adrenal glands are capable of immediately responding to hypothalamic signalling, such that when the hypothalamus gets a signal that a certain hormone is too high or too low in the bloodstream, the adrenals can make up for the difference.  And third, certainly yes, the pituitary still exists to send signals to the gonads.   But cortisol imposes negative feedback on the HPA axis.  Cortisol signals to the hypothalamus to downregulate signalling to the pituitary.  So with cortisol in the system, the production of hormones in gonadal tissue decreases, too. This is the primary long-term pathway by which stress inhibits reproductive function.

Pregnenolone steal, therefore, is at face value a simple phenomenon.  The body gets stressed, and it shunts hormone production into pathways that are meant to be helpful in times of need.    There are levels of complications beneath this action, but in the end it boils down to– as so much of my work does– the fact that stress inhibits reproduction on a variety of fronts.

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HPA axis dysfunction

Posted by on Apr 16, 2012 in Blog, HPA axis | 5 comments

HPA axis dysfunction

There are two primary ways in which the HPA axis can malfunction.  It’s activity can increase, or it’s activity can decrease.

The HPA axis jumps into action when stressed or stimulated.   This is a good thing when the body is faced with short-term stressors.   In this event, adrenal activity increases.   Along with several other key responsibilities, the adrenal glands’s primary purpose is to help us survive in the face of a threat: they rally all of the body’s resources into “fight or flight” mode using cortisol and adrenaline.   Healthy adrenals instantaneously increase heart rate and blood pressure, release energy stores for immediate use, shut down digestion and other secondary functions, and sharpen the senses. But since they are programmed to respond to every kind of stress — physical, emotional, perceived, psychological, environmental, infectious, or any combination of these — a person under chronic stress can get into a fair bit of trouble.  It can knock the whole HPA axis off kilter.  Conditions related to increased activity are: Chronic Stress, Depression, Anorexia, OCD, Anxiety disorders, Excessive exercise, Alcoholism, Withdrawal, Diabetes, Obesity, Metabolic Syndrome, Hypothyroidism.  

The converse is perhaps just as bad.  The HPA axis suffers decreased activity either when hormones tell it to down regulate (as is the case with low leptin signalling!), or it has simply become exhausted by being in a high-stress, hyper-active mode for too long a time period.  Conditions related to decreased activity include: Chronic fatigue, Fibromyalgia, Adrenal insufficiency, PTSD, rheumatoid arthritis, hypothyroidism, asthma, and eczema.

Since cortisol plays a big role in our health and feelings of well-being, and since it also plays a crucial feedback role in up or down regulating the activity of the hypothalamus, stress will be a big piece of the rest of this post.  I’ll talk about different kinds of stress here, and then later detail the effects of cortisol on our bodies.

Clinicians generally divide stress up into four primary categories: emotional stress, sleep disorders, metabolic dysregulation and chronic inflammation.  In my book, they are virtually inseparable.  If you’re signed up for one, you’re almost always signing your life away to all of them.  BUT: they are each handled somewhat differently by the HPA axis.

Mental-emotional stress originates in the brain, and it eeks into the rest of the body via the hypothalamus, which is the hub of connectivity between your brain and the endocrine system.  This drives up the production of ACTH, which stimulates cortisol production later down the line.  Fortunately, this kind of stress is mediated by personality, perception of novelty, uncertainty, control in the situation, and how threatening the stimulus seems.  Low self esteem also makes it easier for the hypothalamus to jump into high gear.

Slow-wave sleep suppresses cortisol release, which is I believe the primary reason sleep is so important for health.   Exposure to chronic stressors results in a disruption of normal hormone fluctuations that occur throughout the day.   This means that cortisol will often jump up at night, creating a vicious cycle of decreased sleep, and therefore increased cortisol, and further decreased sleep, and even greater cortisol levels.  No wonder I’ve been such a wreck for the last twenty years.

The most accepted model of how HPA axes dysfunction  asserts generally that stimulation drives the axis into an overactive state for some time, but that after a while the system becomes unresponsive.   Cells become cortisol-resistant.  This is where the popular term adrenal fatigue comes from, though much of the literature verges on pseudo-science.  While “adrenal fatigue” is certainly problematic, many scientists believe that this is an adaptive, and maybe even productive, response.  Hypercortisolism is bad.   Decreased HPA axis gives the body a bit of a break.  Or at least is intended to.

Why hypercortisolism bites

1)  Cortisol is immunosupressive.  It impairs cytokine production and function, induces the loss of tissues important to immune cell production, and may in fact play a causative role in the development of autoimmune disease.  Being immunosupressive means that cortisol inhibits inflammation.  Generally this is a good thing, but when it goes on for too long, important inflammatory reactions, including the immune reactions I just mentioned, fail to function when they are needed.

2)  Cortisol decreases hormonal output.  It signals to the hypothalamus to down-regulate, such that growth hormone, thyroid releasing hormone, and gonadotropin releasing hormone are released at much lower rates by the hypothalamus.  Yikes!  Without GH you don’t grow; without TSH your thyroid doesn’t work properly; and without GnRH your pituitary fails to signal reproductive activity.   GnRH is a factor in just about every single endocrine disorder.   YEAH.  To top it off, these hormones act as cortisol antagonists.   They typically mitigate the effect of cortisol in the blood.  This makes their absence is even more insidious.  Without them, cortisol can increase without ever being checked.

3) Cortisol increases insulin levels.  This fact, coupled with the decrease in androgens from decreasing hormonal output in general, leads to fat deposition. Visceral fat has buckets full of glucocorticoid receptors, which makes it very easy for cortisol and insulin to shuttle more and more triglycerides into fat cells.  I can’t emphasize how important this is.   The cardiovascular and all adipose-related issues from cortisol hyperactivity increase the all-cuase mortality risk of patients two to three times and decrease life expectancy by several years.

4) Increases in cortisol-induced abdominal fat are associated with an increase in both total oxidative stress and in the number of inflammatory cytokines.

5)  Cortisol can destroy healthy muscle and bone tissue.

Why hypocortisolism bites

1)  Immune system up-regulation.   This can really improve health in some cases.  But up-regulating cellular immunity can induce tissue damage and excessive inflammation via the over-production of pro-inflammatory cytokines.    Low cortisol also makes catecholamine (epinephrine and norepinephrine) levels go unchecked.  These further increase inflammatory cytokines.  They also disrupt T-cell signalling.   The result is susceptibility to inflammatory diseases, including autoimmne diseases, mood disorders, malignancy, obesity  and chronic pain syndromes.  This can also increase susceptiblity to assaults by infectious and environmental pathogens.

2)  Bowel disturbances, PTSD, fibromyalgia, low back pain, burn out, and atypical depression.

3)  High-stress sensitivity, chronic fatigue and chronic pain.    These three occur so frequently and in such concert with low cortisol states that they are referred to as the “low cortisol triad” by some authors.  I know.  Catchy.


DHEA-S is produced in the adrenal cortex.  It is an androgen, and it is considered one of the dominant precursor hormones.  This makes it critical for endocrine and reproductive function.   DHEA-S is produced in other organs, but it’s primary source is the adrenal glands.

High levels of DHEA-S are often associated with hyper-activity of the adrenal glands- so in this case both cortisol and DHEA-S are elevated in the blood.   The HPA axis has started pumping, and it doesn’t know how to stop. Women with PCOS often have high levels of DHEA-S precisely for this reason.   This is bad for them because it makes it much easier to create androgens such as testosterone.  And without parallel increases in estrogen from the ovaries, the excess testosterone will wreak havoc.

Calorie restriction and exercise both also increase DHEA-S levels.   DHEA-S is the primary hormone, and DHEA is the active form.   When calories are consumed, more DHEA is recruited form DHEA-S.   This depletes DHEA-S stories.  So calorie consumption reduces DHEA-S, but calorie restriction will keep levels higher longer.

This is important to note for those of us who restrict calories and exercise frequently.  If we have hormone problems, particularly issue with excess, we might want to think about how to optimize our DHEA-S production.  Too much DHEA-S?  Eat more.    Too little?  Try eating a bit less, or intermittent fasting.

Low levels of DHEA-S are associated with adrenal fatigue and hypocortisolism.  In this case, the HPA axis just can’t do much of anything anymore.   This is bad.  DHEA-S is considered the best “feel good” hormone by many endocrinologists.    And it is a precursor to many hormones.  Moreover, there is a growing body of evidence that healthy levels of DHEA and DHEA-S may help stave off Alzheimer’s disease, cancer, osteoporosis, depression, heart disease and obesity.   You can supplement with DHEA-S if you feel as though you desperately need it.  However, perhaps the best course is to supplement in the meantime while you address the underlying issue of decreased HPA axis activity and adrenal exhaustion.


The pituitary

Because stress is a big deal and everyone wants to know about it, most of the HPA research has focused on cortisol and the adrenals.   But the rest of the axis is important, too.

Decreasing hypothalamic activity down-regulates pituitary activity, which means that the production of sex hormones decreases.   And what causes decreased HPA activity?

One factor is a decrease in leptin levels.  If leptin signalling is weak–ie, if our body fat levels are too low, or if we exercise too often–then the lack of leptin crossing the blood-brain barrier into the hypothalamus signals to the hypothalamus that the body is starving, and certain extraneous bodily functions such as reproduction cease.

A second factor in decreased HPA axis activity is high cortisol levels.  I know that I told you earlier that high cortisol levels are associated with hyper-activity of the HPA axis, so this might be confusing, and you might think they lead to increased sex hormone production, but this isn’t necessarily the case.  Cortisol still always exhibits a dampening effect on the hypothalamus.   The amount of cortisol produced by the body relative to the general activity of the HPA axis is complicated, and has to do with the amount of stress the body is under, how long it has been under that stress, and whether or not the body has lost any of its sensitivity to cortisol.

And finally, HPA axis activity can decrease if it has become exhausted.  This is adrenal fatigue, plain and simple.

In all of these cases, the hypothalamus stops telling the pituitary gland to produce sex hormones.  The pituitary, in turn, stops telling the gonadal tissue to produce hormones themselves.  The end result is overall decreased sex hormone levels.  Sex hormones are necessary for reproductive function, as well as for a variety of other important roles such as waking the body up, putting it to sleep, being in a good mood, and having a good memory.   When sex hormones decrease,  many things can go wrong.  PCOS is one them.  Acne is another.  Loss of libido, too, and also, fertility.   Depression.  Weight gain.  Miscarriage.  Yikes.

The final big system affected by HPA axis dysfunction is the thyroid.  When the hypothalamus is suppressed, thyroid releasing hormone doesn’t get released.  And when the pituitary is suppressed, thyroid stimulating hormone doesn’t get released.  The result is wholesale decrease in thyroid activity, all the way from TSH through T4 and to T3.


So the solution?  Sleep as much as possible.  Eat the appropriate amount of food.   Rest often.  Refuse to be stressed.  I am a firm, firm believer in the power of positivity to make us healthy human beings, and the HPA axis probably plays a big role in that.  Don’t let your co-workers, your boss, whatever, all that nasty crap in your life get you down.  I mean– it’s a million times more complicated than that.  I understand.  But I really do think mitigating those stressors (especially the ones you impose on yourself!) transforms physical health.  No self-hating, no anxiety about your looks, no worries about being perfect.  Your cells will thank you.


*Thank you WomenToWomen for the awesome graphics!

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The HPA axis: an introduction

Posted by on Apr 16, 2012 in Blog, HPA axis | 0 comments

The HPA axis: an introduction

The HPA axis is the means by which many cells communicate with each other, which makes it a very big deal.  From my perspective, for those of us who suffer hormonal imbalances, it is the most important part of our bodies to pay attention to. Here’s why:

If our cells are a kingdom, and our hormones the governors, and leptin the bitchy king, then the HPA axis is the divine law that enables and justifies the whole damn thing. Or we could call it the flashy green code of The Matrix. Or the binding of a book. The point being that when the HPA axis is good it’s good, and when it’s bad all the king’s subjects die. No one wants to die. How do we stop everyone from dying?

The abbreviation HPA axis stands for Hypothalamic-Pituitary-Adrenal axis. It is sometimes called the Limbic Hypothalamic Pituitary Adrenal axis, and also the Hypothalamic Pituitary Adrenal Gonadotropic axis. (Gonadotropic, ladies!) This axis describes the complex interaction between the vast diversity of your hormone hubs, via direct influences and feedback mechanisms.

The Hypothalamus

The hypothalamus, at the core of our brains, is the primary point of connection between the central nervous system and the endocrine system. The hypothalamus releases hormones into the bloodstream. Some of them act on distant tissues, but others go directly to the pituitary gland and in turn tell it what to do. This is why it is often said that the hypothalamus controls the pituitary gland. The secretion of hypothalamic hormones GnRH, gonadotropin releasing hormone, GHRH, growth-hormone releasing hormone, TRH, tryptophin releasing hormone, dopamine, somatostatin, TRH, thyrotropin-releasing hormone and CRH, corticotropin releasing hormone all influence the action of the pituitary and adrenal gland. Hence why they are called “releasing” hormones. The job of the hypothalamus is to conduct the orchestra. It asks for certain things to be played, and if all things are running smoothly, the whole orchestra plays in beautiful concert.

The hormones released by the hypothalamus have specific effects. There are a few that are more relevant for our purposes here. GnRH stimulates LH and FSH activity in the pituitary, which are directly responsible for ovarian activity, ovulation, and menstruation. TRH stimulates the release of TSH–thyroid stimulating hormone–so without this the thyroid gland does not produce what you need. Dopamine inhibits prolactin release, which also acts on the ovaries. And CRH stimulates the release of adrenocorticopin, a precursor to stress hormones. We might say that CRH is the first line of activity in the stress response.

The Pituitary Gland

The pituitary gland is generally divided into two parts, the anterior pituitary and the posterior pituitary. The posterior pituitary releases those distant-action hormones (ADH and oxytocin) which are less relevant for the axis. The anterior pituitary is the one that produces the relevant hormones. Follicle stimulating hormone stimulates the development of follicles on the ovaries and the production of estrogen. Luteinizing hormone triggers ovulation. TSH stimulates production of T4 and T3. In all cases, it’s clear that the receipt of stimulating hormones from the hypothalamus to the pituitary is crucial for reproductive function.

So direct central nervous system stimulation affects pituitary function. One example of this is circadian rhythms and the release of adrenocorticoid to stimulate waking. Yet there is another mechanism that tells the pituitary what to do, and this is feedback from its own system. The hormones directly secreted by the pituitary indicate to the pituitary how much of the product is in the bloodstream. This acts on the pituitary, but also on the hypothalamus, such that high estrogen, progesterone, and testosterone levels can all inform the hypothalamus to reduce production of GnRH. This is helpful often. But in other cases it is absolutely NOT, since high testosterone levels can inhibit GnRH in general, which reduces the production of all pituitary hormones.

The Adrenal Glands

The adrenal glands consist of two distinct parts: the adrenal medulla, which secretes catecholamines directly into the blood, which I’ll touch on a bit later, and also the adrenal cortex, which secretes steroid hormones. The primary steroid hormones are cortisol, corticosterone and DHEA, the precursor to adrenal sex hormones.

Approximately 90 percent of the cortisol in our systems is “bound.” The remaining 10 percent is free, and it’s what is biologically active. Cortisol is metabolized in the liver, and it has a half life of 60-90 minutes! Isn’t that amazing? If we are not constantly stressed, then the hyper-stressed states we enter into from an immediate event are only supposed to last for 60-90 minutes. Amazing.

Cortisol is important for a number of reasons. Without it, we die. Here are some of its functions:

1. Metabolism.  Cortisol and other glucocorticoids exert anabolic effects– that is, gluconeogenesis and glycogenesis– on the liver, and catabolic effects– or proteolysis, and lipolysis– in the tissue. What this means is cortisol stimulates activity that utilizes energy sources. Proteolysis eats muscle tissue, which is generally bad, but lipolysis eats fat tissue, which is usually good. Gluconeogenesis and glycogenesis make glucose and glycogen in the liver.

2.  From the stimulation of cortisol, glucose output by the liver increases and glucose uptake by other tissues decreases. Another way to say this: cortisol increases blood sugar. Insulin is secreted in response to blood sugar, in order to mitigate the effects.

3.  Cortisol influences the immune system and inflammatory responses. Cortisol and all other glucocorticoids suppress the synthesis of arachnidonic acid, the precursors to a number of compounds involved in the inflammatory response.  They also decrease the key compounds interleukins and gamma interferon, which are crucial for the immune response.

4.  Cortisol also decreases REM sleep significantly: high concentrations in the blood can cause insomnia and, duh, decrease mood. Cortisol secretion increases in response to stressful stimuli. It is in fact crucial for survival in extreme circumstances. The reasons for this are not well understood, especially in light of the fact that cortisol inhibits immune function. The best guess is that cortisol is required for initial metabolic responses to stress–but that, right, we overdo it. Surprise.

ACTH and cortisol are released in irregular pulse throughout the day. The biggest pulse occurs in the early morning, and starts a few hours before waking. The lowest levels of ACTH in the blood occur right around the time of falling asleep (in someone with regular circadian rhythms.) Spikes in cortisol about half as large as though during waking occur each time you eat, roughly correlated to how much you eat. DON’T freak out about your meals because of this. Your body handles cortisol quite well. No irrational panics allowed. Just– take note. This is one reason why both grazing and bingeing are not optimal behaviors.

This whole system is moderated by negative feedback, as in most of the body’s systems. When the hypothalamus detects enough cortisol, CRH (in the hypothalamus), and therefore ACTH (in the pituitary), and therefore cortisol (in the adrenals) production, are all decreased. You understand, then. The HPA axis is a delicate flower.

Finally, there is a whole class of adrenomedullary hormones, such as catecholamines (epinephrine and norepinephrine), we haven’t talk about. But they’re important, too. The first step in their biosynthesis is catalyzed by tyrosine. Don’t be in tyrosine (an amino acid). It’s important.  Epinephrine and norepinephrine both increase blood glucose concentrations and metabolic rate.  Epinephrine increases cardiac output, vasodiliation in skeletal muscle and liver but vasoconstriction in other vascular tissues– so essentially it shunts blood to skeletal muscle and the liver. Norepinephrine causes primairly vasoconstriction, which results in increases in blood pressure–ie, a reduction in cardiac output.

Epinephrine and Norepinephrine are activated by “fight or flight” situations, ie, our regular lives. Their production is, here’s another surprise, initiated by the hypothalamus. BUT these babies aren’t regulated by negative feedback. This is important. Cortisol will decrease in response to high cortisol levels. Epinephrine and norepinephrine instead can just keep on rising.  Ack, ack, ack.

So that’s a review of the HPA axis.  It’s complicated as all hell.  But even more than complicated, it is important.  The HPA axis runs the whole hormonal game, and therefore the vast majority of your reproduction and metabolism.    It responds to stress, and it helps you mitigate stress.  It responds to hormonal input, and helps you mitigate hormonal problems.   It is sensitive to signalling from all over your body.  These are all awesome things, but it also means that disruptions, can really throw you off.

The HPA axis significantly effects your thyroid gland, how you metabolize food, how much estrogen and testosterone you produce in your ovaries, and how much stress hormones and sex hormones you produce in your adrenals.  I’ll talk about those issues in my next post.

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