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

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.



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

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.

So what can you do if your sleep is dysregulated?  There are some things that can help with sleep. Of course, if there are underlying issues, those may need to be addressed. A good, whole foods diet like the one I detail in Sexy By Nature can help you with that.

Putting away electronic devices or wearing blue blocking glasses before bed can help melatonin production which will help you fall asleep easier as well.

If weight loss is necessary to help your sleep, Weight Loss Unlocked is also incredibly helpful.



The HPA axis: Psychological Stress and Hypothalamic Amenorrhea

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 pschyological 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, causing stress hormones to be released and sex hormone production to decline.

Exercise and weight loss disturb the HPA axis via metabolic disturbance. Although it seems logical that specific cascades exist for different types of stress — for the psychological or the physical — there is currently no method for clearly delineating psychogenic from metabolic stress. So far as we can tell, they are both equally damaging to sex hormone production, and can cause hypothalamic amenorrhea.


Hypothalamic amenorrhea: the power of stress

One way to test the potence of pyschosocial stress on female fertility is with primate studies. 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 rung 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. (An important side note: 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.

Kinds of stress that cause hypothalamic amenorrhea

There are many stressors associated with stress-induced amenorrhea. 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. This is “intrapsychic stress.”

(To read about how I got rid of my own intrapsychic stress and help my clients do the same, check out my best-seller for women’s confidence, Sexy by Nature, here!)


“Intrapsychic” stress is the nebulous stuff that women impose on themselves–encouraged by society or otherwise–and it kills the HPA axis. 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. 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.

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.

I am going to mention my book again here, because it really has been so helpful for so many women dealing with this. Really. Take a look. 🙂 Here: Sexy by Nature.

The intersection of psychological and physical stress

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 100%.  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.  Not all, but a significant portion of, women who suffer from hypothalamic amenorrhea need psychological healing, far more than anything else. After that, not only do stress levels fall, but healthier eating habits become the norm.

For more on how to recover from HA and make healthier eating habits become the norm, check out this post, or my confidence- and love- inspiring book on Amazon, Sexy by Nature.

The HPA axis: Metabolic Distress and Hypothalamic Amenorrhea

The HPA axis: Metabolic Distress and Hypothalamic Amenorrhea

The hypothalamic-pituitary-adrenal (HPA) axis (you can read an introduction to it here) 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. If the hypothalamus puts up a stop sign, then sex hormone levels fall.

Worse, when this stop sign is up, cortisol is usually being produced by the adrenals. This negatively influences the activity of both the hypothalamus and the pituitary glands.

Hypothalamic amenorrhea– or the loss of menstruation via disturbance to the HPA axis–affects 5 percent of women of reproductive age. Subclinical women (women who do not fully meet the requirements for the condition but nevertheless suffer from it in some way or another) 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.

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.

Chronic stress itself is divisible into two distinct categories: psychological stress and metabolic stress.

Psychosocial stress is caused by mental, emotional, and social factors. Metabolic distress is caused by energy deficits–which are caused by restricted food intake and excessive exercise. Basically, anything that significantly deprives a woman’s body of caloric energy is a metabolic stress.

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

You can also read more on how to regain fertility through food and lifestyle by clicking here for my bestselling book, Sexy by Nature.

Hypothalamic Amenorrhea in general

The point of the HPA axis is to metabolically mobilize individuals in stressful circumstances.  It causes stress hormones to go up – which can energize you!

In stressful situations, stress hormone levels rise, and sex hormone levels fall.

In one study, the degree of ovarian compromise women suffered was in a precise inverse relationship with observed cortisol levels.  That’s pretty amazing.  Cortisol performs 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. 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.

So that is stress and the hormone cascade in a nutshell. Hormones are produced like dominoes. If somethin goes wrong at the beginning of the set, then none of the dominoes are going to fall in the right way.

Exercise, weight loss, and metabolic stress

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 do not ovulate 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, 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.

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.

To read about healthy ways to lose weight as a woman, check out my book Weight Loss Unlocked.

Biochemical implications of excess energy expenditure

Metabolic imbalance occurs when energy expenditure exceeds energy intake. 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.

The hormones from fat cells implicated in energy regulation include leptin, adiponectin, and resistin. Leptin 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 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.

How to increase leptin levels

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 (leptin) 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, I mispoke. 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.

The solution is to eat all the things. It is to err on the side of eating more rather than less. It is to reduce stress as much as possible. It is to refuel properly after workouts.

You can read about HA and psychological stress here.

You can read more about how to recover from HA (from all causes) here.

You can check out my best-selling book on how to get your natural swagger and fertility back at Amazon here and my healthy weight loss book here.



HPA axis: what is pregnenolone steal?

HPA axis: what is pregnenolone steal?

Pregnenolone steal is not a term commonly used by medical professionals and doctors. Yet if described to them, they would happily admit that it is a real phenomenon that affects millions of people.

In fact, it affects every person (and especially every woman, since female hormones are more sensitive than male) who has ever been stressed.

In my bestselling book Sexy By Nature, I detail my own struggle with pregnenolone steal and how I ultimately overcame it.  You can check that out here.  I also have written extensively about other women’s hormonal issues, including PCOS, which you can read about here.

Pregnenolone steal is a problem because it is one of the primary ways in which the body can be physically handicapped by mental stress.

This is not good news for anybody.

Pregnenolone steal: the human stress response

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 digestion. It is the immediate “flight or fight” response. It’s largely a nervous system activity.

Second, it occurs in hormone form.

The hypothalamus, the “hormone command center” of the brain, decides to be stressed out, and gives marching orders according to its feelings.

Immediately, the adrenal glands respond by pumping out cortisol (the main stress hormone) and adrenaline. 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.

Pregnenolone steal: why and how

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

It steals it! Literally.  It “steals” pregnenolone. Pregnenolone is a precursor hormone. It is used by the body to make both stress and sex hormones. In times of stress, the body diverts a lot of the pregnenolone toward stress hormone production and away from sex hormone production.

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.

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.

Second, 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.

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.

Stress can be managed, especially if it isn’t chronic.  For example, a good magnesium supplement or epsom salt bath can do wonders to help relieve stress.  Aromatic oils and even getting enough sunlight (or Vitamin D3 through a supplement) can also help.

If you have chronic stress and issues with fertility, it is worth looking into where and how you can cut stress out of your life.

You can read more about the effect of stress on health – a whole lot more – in my best-selling book on the topic, Sexy by Nature, here. In it, I describe how I personally overcame my pregnenolone problem and got my fertility, libido, and clear skin back.