Shattering the Myth of Fasting for Women: A Review of Female-Specific Responses to Fasting in the Literature
One of the more esoteric but much beloved tools in the paleo dieter’s tool-kit is intermittent fasting. Intermittent fasting is the practice of maintaining overall caloric intake while consuming those calories in fewer meals or in reduced time windows. Some examples include 10, 8, or 5 hour eating windows throughout the day, or perhaps eating just two meals each day: one in the morning, and one at night. The evolutionary premise is that humans evolved to optimize their health under less-than-optimal conditions. Fasting may have played a significant role in ancestral human physiology.
The modern-day scientific correlate appears promising, too. Most people are aware that a calorie-restricted diet has the ability not just to decrease body weight but also to lengthen a human life. Emerging research is beginning to show, however, that intermittent fasting is just as effective as calorie restriction in ensuring these health benefits, and amazingly enough without any of the psychological crippling side effects practitioners of calorie-restriction often experience.
Intermittent fasting also may benefit the fight against cancer, the ubiquity of diabetes, and individuals’ immune function. Here is another excellent, up-to-date review. It is wholly understandable that fasting is all the rage these days.
I have a specific interest in intermittent fasting because of what I have witnessed in women in the PfW community. Many women find that with intermittent fasting comes sleeplessness, anxiety, and irregular periods, among a myriad of other symptoms hormone dysregulations. I have also personally experienced metabolic distress as a result of fasting, which is evidenced by my interest in hypocretin neurons. Hypocretin neurons have the ability to incite energetic wakefulness, and to prevent a person from falling asleep, should his body detect a “starved” state. Hypocretin neurons are one way in which intermittent fasting may dysregulate a woman’s system.
Because of all these experiences I was having myself and hearing about in others, I undertook investigating both a) the fasting literature that paleo fasting advocates refer to, and b) the literature that exists out in the metabolic and reproductive research worlds.
What I found is that the research articles cited by Mark’s Daily Apple (and others), focus on health benefits such as cancer-fighting properties, insulin sensitivity, and immune function. These phenomena are not guaranteed in the literature– both mice and humans don’t always lose weight, and sometimes they even gain weight with IF regimes–but more often than not significant improvements are noted in body weight and with markers such as inflammtory cytokines, HDL, LDL, triglycerides, and fasting insulin levels. This is wonderful, and I am glad these issues are being brought to greater light.
However. I was struck by what seemed like an egregious sex-based oversight in that MDA post I linked to above. MDA cites this article as a “great overview” of the health benefits of intermittent fasting. This startled me because the article MDA cited was for me one of the strongest proponents of sex-specific differences in response to fasting. This occurred in two striking areas: a) women in studies covered by the review did not experience increased insulin sensitivity with IF regimes and b) women actually experienced a decrease in glucose tolerance. These two phenomena mean that women’s metabolisms suffered from IF. The men’s metabolisms on the other hand improved with IF across the board. Recall that the review was reported by MDA as “a great overview of benefits [of IF].”
Secondly, In another fasting post at MDA, of which there are many, the health benefits of fasting are listed and reviewed, but the sex-specific aspects of the hormonal response went unmentioned, and reproduction/fertility/menstrual health wasn’t mentioned at all. This is not to say that Mark is not attentive to who should and who should not be fasting. He knows very well and cautions people against the dangers of fasting while stressed. Still, the mere fact of being more sensitive to the strains of fasting simply by being a woman is, I would assert, pretty important for a woman who is contemplating or already practicing IF. This goes nearly unmentioned in the blogosphere.
Beyond reporting biases in the blogosphere, there remains an even greater problem (perhaps even the cause of the blogosphere reporting bias) of a significant testing bias in the fasting literature. Searching “men” + “intermittent fasting” in a Harvard article database yields 71 peer-reviewed articles. Searching “women” yields 13, none of which are a) solely about women b) controlled studies or c) about more than body weight or cardiovascular benefits. The animal studies are more equitable, but also a bit less applicable to human studies.
It is well-known in both the research and the nutritional communities that caloric restriction is horrible for female reproductive health. This is not news. But what of fasting regimes? Should women go long periods without eating, even if maintaining normal caloric input?
The few studies that exist point towards no.
It’s not definitive, since the literature is so sparse, and it necessarily differs for women who are overweight versus normal weight (and who have different genetic makeups regardless), but when it comes to hormones, women of reproductive age may do well to err on the side of caution with fasting.
What follows first is a brief review of what can be gleaned in sex-specific responses to fasting in animal studies. Afterwards is what has been concluded by the few relevant human studies.
Mice and Rats
First up is a study that demonstrates the hippocampal changes of calorie restriction and intermittent fasting (alternate day fasting, with ad libitum eating on feeding days) for both male and female rats. The basic premise is this: in a “starvation” state certain brain changes parallel behavioral changes. The study found that they were different for male and female rats. For male rats the change in hippocampus size, hippocampal gene expression, and ambulatory behavior was the same no matter what kind of restricted diet they were on, but for female rats, the degree of change in brain chemistry and in behavior was directly proportional to degree of calorie intake, demonstrating the unique sensitivity of female rats to the starvation response.
“ The organization of the females’ response to the energy restricted diets is suggestive of some underlying mechanism that may allow for an organized, pre-programmed, response to enhance survival in times of food scarcity. Comparatively, the males’ genetic response was less specific, suggesting that the males respond to a general stressor but they seem to lack the ability to discriminate between a high energy and low energy stressor.”
Moreover, “IF down-regulated many gene pathways in males including those involved in protein degradation and apoptosis, but up-regulated many gene pathways in females including those involved in cellular energy metabolism (glycolysis, gluconeogenesis, pentose phosphate pathway, electron transport and PGC1-α), cell cycle regulation and protein deacetylation.” In this study, both male and female rats gained small amounts of weight on IF diets.
For female rats, even in the most innocuous form of restriction–intermittent fasting–significant physiological changes take place. Male rats do not experience as dramatic hippocampal and general brain chemistry change as female rats do, and their behaviors, specifically their cognition and their dirunal and nocturnal activity, do not change. Female rats, on the other hand, “masculinize.” They stop ovulating and menstruating. They become hyper-alert, have better memories, and are more energetic during the periods in which they are supposed to be sleep. Theoretically, according to these researchers, this is an adaptive response to starvation. The more the female rats need calories– or at least the more their bodies detect a “starvation” state– the more they develop traits that will help them find food. They get smart, they get active, and they stop sleeping.
In a follow-up study conducted by the same researchers who explored the masculinzation of female rats, the researchers analyzed the gonadal transcription of male and female rats subjected to IF regimes. They found that male reproductivity up-regulate in response to the metabolic stress, and that the female reproductivity down-regulated. In response to the female rats become infertile and masculinized, male rats become more fertile. In the researchers’ own words: “our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment.”
In the final relevant IF rat study I could find, researchers subjected rats to the same diets– to 20 and 40 percent CR diets, as well as to alternate-day fasting diets, and monitored them over the long term for hormonal responses. The results were striking. Below is the abstract in full because it’s so powerful:
Females and males typically play different roles in survival of the species and would be expected to respond differently to food scarcity or excess. To elucidate the physiological basis of sex differences in responses to energy intake, we maintained groups of male and female rats for 6 months on diets with usual, reduced [20% and 40% caloric restriction (CR), and intermittent fasting (IF)], or elevated (high-fat/high-glucose) energy levels and measured multiple physiological variables related to reproduction, energy metabolism, and behavior. In response to 40% CR, females became emaciated, ceased cycling, underwent endocrine masculinization, exhibited a heightened stress response, increased their spontaneous activity, improved their learning and memory, and maintained elevated levels of circulating brain-derived neurotrophic factor. In contrast, males on 40% CR maintained a higher body weight than the 40% CR females and did not change their activity levels as significantly as the 40% CR females. Additionally, there was no significant change in the cognitive ability of the males on the 40% CR diet. Males and females exhibited similar responses of circulating lipids (cholesterols/triglycerides) and energy-regulating hormones (insulin, leptin, adiponectin, ghrelin) to energy restriction, with the changes being quantitatively greater in males. The high-fat/high-glucose diet had no significant effects on most variables measured but adversely affected the reproductive cycle in females. Heightened cognition and motor activity, combined with reproductive shutdown, in females may maximize the probability of their survival during periods of energy scarcity and may be an evolutionary basis for the vulnerability of women to anorexia nervosa.
They also found this:
The weight of the adrenal gland was similar in rats on all diets; however, when normalized to body weight CR and IF diets caused a relative increase in adrenal size, the magnitude of which was greater in females, compared with males.
The testicular weight was unaffected by any of the diets. In contrast, both CR diets and the IF diet caused a decrease in the size of the ovaries.
And this, bearing in mind that “daytime” for nocturnal rats is “nighttime” for humans:
The daytime activity of females was doubled in response to IF, whereas the IF diet did not affect the activity level of males. Nighttime activity levels of males and females were unaffected by dietary energy restriction.
Uterine activity was monitored daily with vaginal smear tests; cyclicity was scored as regular, irregular, or absent. The mild energy-restriction diets (20% CR and IF) significantly increased the proportion of animals displaying irregular cycling patterns, whereas the 40% CR animals displayed an almost complete loss of estrous cyclicity.
In males, corticosterone levels were elevated only in response to the 40% CR diet, whereas in females corticosterone levels were significantly elevated in response to all three energy-restriction diets, suggesting a relative hyperactivation in females of the adrenal stress response to reduced energy availability.
For lipids, all the rats did well: “Collectively, these data suggest that atherogenic profiles of both males and females are improved by dietary energy restriction.” Interestingly, too, as they pointed out in the abstract, human females also perform cognitively much “better” (memory and alertness) on CR and IF diets than on normal feeding schedules.
Some caveats to this study: A) They are rats. B) They are somewhat “metabolically morbid” rats, which may make them more susceptible to disease. C) The rats were allowed to eat ad libitum on the IF days, but they simply did not meet their caloric requirements this way. So while it is a somewhat natural form of IF, it is still calorically reduced, such that that must be taken into account when gasping in horror at the hormonal responses of IF-ing female rats.
The Few Human Studies
I mentioned above that through the same review that MDA used as a “great overview” of IF benefits I found harmful metabolic effects for women subjected to alternate-day fasting regimes. This is the study:
Heilbronn et al found that with IF insulin sensitivity improved in men (21 participants) but not in women (20 participants): after three weeks of alternate day fasting, insulin response to a test meal was reduced in men. Women experienced no significant change. “It is interesting that this effect on insulin sensitivity occurred only in male subjects,” they report.
The IF regime, moreover, was not just neutral for women but was downright harmful, specifically with respect to glucose tolerance:
“Another diabetes risk factor that has shown a sex-specific effect is glucose tolerance. After 3 weeks of ADF, women but not men had an increase in the area under the glucose curve. This unfavorable effect on glucose tolerance in women, accompanied by an apparent lack of an effect on insulin sensitivity, suggests that short-term ADF may be more beneficial in men than in women in reducing type 2 diabetes risk. ” The opening line of their discussion reads: “Alternate day fasting may adversely affect glucose tolerance in nonobese women but not in nonobese men.”
In a follow up study, Heibron et. al studied the effects of alternate-day fasting on cardiovascular risk. When human subjects fasted on alternate days for another three week period, circulating concentrations of HDL cholesterol increased, whereas triacylglycerol concentrations decreased. This is a good thing. However, the shifts in lipid concentrations were shown to be sex specific: ie, only the women had an increase in HDL-cholesterol concentrations, and only the men had a decrease in triacylglycerol concentrations.
The most recent review of IF agrees with my conclusion: sex-specific differences in metabolism exist and need to be studied further.
This study of alternate day fasting included 12 women and 4 men. In eight weeks, body weight decreased by about 10 pounds, and body fat percentage decreased from 45 to 42. Blood pressure decreased, total cholesterol, LDL cholesterol, and traicylglycerol decreased. These people were significantly obese, which limits the results of this study to an obese population. However, “perimenopausal women were excluded from the study, and postmenopausal women (absence of menses for >2 y) were required to maintain their current hormone replacement therapy regimen for the duration of the study.” (Their words, my emphasis)
The one, big study of intermittent fasting conducted on men and women looked at differences between isocaloric feeding schedules: 3 meals/day feeding versus 1 meal/day.
The study focused on body weight composition, blood pressure, and body temperature in subjects. Subjects were fed isocalorically either one meal each day or three meals each day. All subjects were between 40 and 50 years old (excluding women of reproductive age), and between BMIs of 18 and 25. They ate, so far as I can tell, a healthy diet with 35 percent fat, PUFA < MUFA < SFA. Only 15 of the original 69 completed the study. As for the results,
“Systolic and diastolic blood pressures were significantly lowered by ≈6% during the period when subjects were consuming 3 meals/d than when they were consuming 1 meal/d. No significant differences in heart rate and body temperature were observed between the 2 diet regimens. Hunger was enormously larger in the one meal/day than in the three meals/day group. ”The 1 meal/d diet was significantly higher for hunger (P = 0.003), desire to eat (P = 0.004), and prospective consumption (P = 0.006) than was the 3 meals/d diet. Feelings of fullness were significantly (P = 0.001) lower in the 1 meal/d than in the 3 meals/diet.” Body weight dropped only four pounds after several months. Cortisol dropped, but Total, LDL, and HDL cholesterol were 11.7%, 16.8%, and 8.4% higher, respectively, in subjects consuming 1 meal/d than in those consuming 3 meals/d.
In sum: patients on the one meal/day regiment were unhappy, hungry, lost a little bit of weight, increased cholesterol. This was a small sample, included ~menopausal women, and all people of normal body weight.
All that being said, that’s it. That’s all that exists. Women don’t have much to go on. First, a couple of rodent studies have looked at alternate-day fasting for male and female rats and found significant negative hormonal changes occurring in the females. Second, human studies on alternate day fasting have not been conducted on women of reproductive age at all, nor have any studies analyzed reproductive responses to fasting. Third, the few studies that have been conducted on non-obese women have demonstrated that their metabolic responses are not nearly as robust as those of men, and may in fact be antagonistic to their health.
This post has focused on sex-specific responses to fasting. Another important distinction to make is between different body weights. Overweight and obese patients appear to experience significant improvements with IF regimes, but normal weight patients do not show the same across-the-board benefits. For women this may be a particularly sensitive issue. Overweight women may experience metabolic benefits, whereas normal weight women do not. I suspect that that may roughly be the case, but who knows. Honestly, no one.
The solution, then, in moving forward, is to look at options, to be honest about priorities, and to listen to one’s body with awareness and love. Is fasting worth trying if a woman is overweight and trying to improve her metabolic markers, and so far hasn’t had much success? Perhaps. Should it be undertaken if a woman is of normal weight? What if she is a light sleeper? What if her periods begin to dysregulate? Or stop? What if she starts getting acne, getting a stronger appetite, or losing her appetite altogether? These things happen, and I see them in women who fast and contact me time and time again.
We women (people!) should be honest with ourselves about our priorities, and act constantly with our mental and physical health foremost in our minds. All women are different. But the literature is so sparse in this area that we cannot make any real statements or predictions about the effects of fasting, other than that we just don’t know, and that we should continue to emphasize the centrality of awareness, caution, and loving nourishment in moving forward.
IF is one realm in which the female body has unique characteristics and needs that demand attention. There are boatloads of others. If you’re interested in reading about the collective set of them and learning how to optimize female skin, weight loss, and hormone balance, for a few examples, you could do worse than my forthcoming book, Sexy by Nature, which hits shelves on March 18 and is available for pre-order on Amazon @here.
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.