Intermittent fasting for women – Is it really that bad?

I decided to do this post in English (Danish translation may follow ;o) as the suitability of intermittent fasting for women has been quite a hot topic in the blogosphere. In particular, several high-profile bloggers have posted blogs specifying how Intermittent fasting (IF) is inappropriate for women or at least more inappropriate than for men, the most notable one being Stefani Ruper’s post at PaleoforWomen (PfW). That post in particular has been quoted in a large number of other prominent health/fitness blogs, like Marks Daily Apple, breakingmuscle.comthebulletproofexecutive.com, some more horribly one-sided than others. As Stefani’s post has been the source of most of this IF for women-criticism, this post will deal with the points she put forth in her original blog post.

I have really made an effort to be thorough in this post as I hope this be the post everyone links to in response to the post at PfW ;o) This post is kind of science-heavy, but I hope you’ll endure. Make a cup of coffee and sit back, while Dr. Muscle goes elbow deep (in the science, that is ;o)

introduction

First of all, let me state that I do not have an agenda claiming that fasting diets are better or more suitable for weight loss than other regimes. Also, I do not claim that the response to fasting diets are similar between genders. Actually, I’m pretty sure that there are gender differences. However, I’m quite sure that IF is not significantly worse for health or weight loss in women than men, as is stated in a number of these blog posts.

I found it necessary to write this post, since Stefani’s post has become a mainstay of IF-criticism and I think her arguments are actually quite weak. Also, her experiences from the PfW community does not match my own. As my Danish readers probably knows, I’m a co-author of a Danish book (“1-dagskuren”) and for that book we interviewed almost 100 people practising various forms of IF. Amongst those, we encountered very few adverse reports reminiscent of Stefani’s (the most common complaints were gastric problems upon resuming eating and headaches on fasting days most likely attributable to dehydration and even those weren’t that common).

STEFANI’S CRITIQUE AT PFW

Stefani starts of telling that her post is based on her experiences in the PaleoForWomen community, where she has experienced a lot of women having problems with sleeplessness, anxiety and irregular periods, in order words, generalized stress symptoms and impaired reproductive health – bad stuff. This set her on a quest into the scientific literature, which raised a number of specific points, that can essentially be broken into three separate areas:

  • CLAIM 1: A particular scientific study (the Heilbronn study) comparing men and women showing that males have favourable metabolic reactions and female have unfavourable reactions to alternate-day fasting.
  • CLAIM 2: The metabolic fasting responses observed in scientific studies are not representative to women because they predominantly use male subjects.
  • CLAIM 3: She claims that the gender-specific neuroendocrine response (especially  increased stress and impaired reproductive health) to alternate-day fasting in rats is also applicable to humans.

I will try to deal with these specific points the best I can, but in order to do so, we need to go through the very basics of fasting.

Basics of fasting metabolism

In normal (non-fasting) humans, the body runs on approximately 60-70% fat and 30-40% carbs in the resting state. This distribution changes towards a higher reliance on glucose, as the exercise intensity increases.
In women, resting metabolism is skewed slightly towards more to the “fat side” than is the case for men. This is one of the reasons it is said that female metabolism is better suited for ultra-endurance events. During fasting, the body’s carbohydrate stores are quickly depleted (

 Short-term fasting

During short-term fasting it has also been shown that women more readily adapts to metabolizing fat as the primary substrate. Thus, in short-term fasting, women have larger decreases in insulin and larger increases in glucagon, cortisol and growth hormone (all of these hormones serve to mobilize energy stores), and lower levels of circulating amino acids, compared to men (Mittendorfer et al 2001, Merimee et al 1973, Merimee et al 1978, Soeters et al 2007). All of these traits support the notion that women are better at changing to fat utilization in the short run. While one might think that the cortisol increases would possibly result in a greater breakdown of muscle, the lower circulating levels of amino acids indicates that this is not the case, since the only source of plasma amino acids during fasting, are derived from tissue breakdown. This is further confirmed by lower excretion of total nitrogen in urine (urine nitrogen is produced during protein breakdown).
In short, these gender differences in humans generally reflect the conditions in rodents, as described in an early review by Katherine Hoyenga (Hoyenga et al 1982). While I don’t know if this difference is present in all other vertebrates, I suspect that it’s partly related to the fact that in mammals, the mother should be able to mobilize fat efficiently during breastfeeding and that this effect has some carryover during times of famine.

What about long-term fasting or caloric restriction?

There are few studies looking into human sex differences in the response to sustained fasting. The only one I have been able to dig up, is the study by Runcie and co-workers (Runcie et al 1974) with 30 days of fasting in 76 subjects of both genders. This study shows that sustained fasting is tolerable across genders and that the relative weight loss is comparable between men and women. Unfortunately, the scientists in that study did not look into hormone levels, subjective experiences or habitual activity levels. The authors did comment that the females appeared slightly more heterogeneous with respect to habitual activity levels, both before and during the fasting period, but did not claim that the average female response appeared different from the male’s. Also, there are a number of newer, shorter duration fasting studies (3-14 days). In general they report weight loss (DUH!) and an improved metabolic profile.

An interesting point should be made at this time; following sustained fasting, glucose tolerance upon resuming feeding is impaired for a short time (Horton et al, 2001). While there is no science on how long this effect persists, committed fasters with blood glucose meters have told me that this happens only during the first meal following a fast. Thus, although, the metabolism seems to benefit overall, there is a transient impairment of glucose control.

Glucose and insulin response to glucose challenge following 72 hour fasting (Horton et al, 2001)

Glucose and insulin response to glucose challenge following 72 hour fasting (Horton et al, 2001)

Furthermore, there are experiences from long-term caloric restriction that may also help elucidate this topic. In this field there is two studies of particular interest: The BIOSPHERE 2 project and the CALERIE study. BIOSPHERE 2 was a project in which 8 adults (scientists) were enclosed in a sealed habitat, essentially a huge greenhouse, and stayed there for 2 years, without receiving external supplies. During their stay in the habitat, the researchers came to realize that the amount of food the habitat could supply was not adequate for their normal energy expenditure and thus they came to rely on involuntary caloric restriction for the majority of the 2 years (Walford et al 2002).The CALERIE trial is a clinical trial being done in the USA under the National Institute of Aging, where several hundred normal weight, adult subjects are undergoing 2 years of 25% caloric restriction. The trial finished in 2012 and the first publications with results are in preparation as I write this, but there are already several publications describing the inclusion process and study design. Both of these projects have thus resulted in a number of scientific studies and amassed considerable public media awareness. As far as I know, there’s been no mention of the women suffering more than the men during their enclosure or being more prone to generalized stress. While this is not evidence by itself, it should be noted that if serious adverse reaction like prolonged loss of the menstrual cycle arose, it would have to be reported, as these were both official clinical trials registered under Clinicaltrial.gov and the NIA.

You might think, “what is the relevance of sustained fasting and chronic caloric restriction” and the answer is that with intermittent fasting, some of the same metabolic and endocrine adaptations manifest, depending on the total fraction of time you are fasting. Therefore, if human females were generally more susceptible to the negative aspects of fasting during prolonged fasting or caloric restriction it would be more likely that this would also be the case during IF… and this ties beautifully into the next paragraph…

Then what about intermittent fasting?

Well, there are several kinds of intermittent fasting. The type most frequently used in scientific studies is alternate-day IF (ADF), while the types being used in the public are mostly either 1-2 weekly fasting days or part day fasts, like the 16:8 fast. As far as the state of the art goes, there is a bunch of studies on ADF, one or two on intermittent fasting reminiscent of 5:2 or 6:1 fasting in humans and only one reminiscent of part-day fasting (e.g. 16:8 or 19:5 fasting) at the time of writing.

Well, the results from the ADF IF studies in overweight individuals have generally shown  improvements in the metabolic phenotype in men AND women (improvements in cholesterol, LDL particle size, fasting insulin and glucose and blood pressure) (Eshginia et al, 2013; Varady et al 2009;  Varady et al, 2010; Varady et al, 2011; Johnson et al 2007). Also, the 6:1 fasting study (done in women) by Klempel (Klempel et al 2012) showed solid improvements in health biomarkers, as did the 5:2 study (done in women) by Harvie (Harvie et al, 2011).

In summary, fasting is safe and IF diets does work for weight loss and health biomarkers for men AND women. Also, they appear to have similar health effects to other energy restriction modalities resulting in similar weight losses.

Getting to Stefani’s points

Ok, having run you through the basics I’m ready to address the specific critique points that Stefani took up at the PfW blog:

  • CLAIM 1: the Heilbronn study shows that males have favourable metabolic reactions to alternate-day fasting.

The Heilbronn study is an alternate day fasting study conducted with normal-weight adults (8 men, 8 women) for 3 weeks with baseline measurements at day 21 (an eating day) and day 22 (a fasting day). this resulted in an average weight loss of 2.1 kgs. It resulted in two publications, one dealing with the effects of a glucose challenge and one dealing with fasting state numbers and energy expenditure numbers (Heilbronn et al, 2005a and 2005b). In the former of these studies, they showed some apparently rather unsettling results regarding glucose control which forms a major part of Stefani’s IF-criticism. In the study women appeared to have impaired glucose clearance following a glucose challenge (no change in men), and no change in insulin response (improvement in men). See the figure below:

Figure from Heilbronn et al 2005, showing an impaired glucose control response on a fasting day following 3 weeks of alternate-day fasting

Figure from Heilbronn et al 2005, showing the response to a glucose challenge before the study and after (on a fasting day) following 3 weeks of alternate-day fasting, showing an improvement in insulin response in men (no change in women) and and impaired glucose clearance in women (no change in men) (Heilbronn et al, 2005a and 2005b)

While this may in fact be true, I think the results in overweight and obese women from other studies, where ADF generally improves the metabolic phenotype should warrant some scrutiny. Specifically, two points comes to mind. Firstly, if you look at the curves above you’ll notice that for the insulin response  in men before the study (“pre men”) the levels peak rather high, and that the variation is also quite big. This means that there is high variation amongst the men and most likely, that just a few of them of them have a very big insulin response, indicating that they were less well off, metabolically.

Indeed, if you look at the baseline characteristics (below), you’ll see that the men were considerably less metabolically fit than the women, being slightly overweight, having higher relative body fat percentages (25% is normal for women, 22% is kind of high for men), having higher resting glucose and higher resting insulin. Having a resting insulin of 10.5 is, although not diabetic, certainly not “good” and just as certainly, a lot poorer than the women, explaining why the men seemed to improve and the women didn’t.

Baseline characteristics of the participants in the Heilbronn study

Baseline characteristics of the participants in the Heilbronn study

Indeed, another study using younger, leaner healthier men subjected to ADF for two weeks and then measuring insulin and glucose dynamics using an euglycemic clamp, showed no improvement in insulin sensitivity or glucose clearance in men following IF (Soeters et al, 2009). An euglycemic clamp is a more controlled way to exposed people to a glucose challenge – clamping is normally considered a stronger scientific model.

Secondly, considering that women are already more adept at mobilising fat than men and that we know that even short periods of fasting can induce transient impairment of glucose clearance, it is rather likely that the impaired glucose clearance observed in women is caused by the transient fasting effect, and that this effect is masked in the men because of their higher glucose response at the beginning of the study due to their poor metabolic phenotype. If you look at the fasted state insulin and glucose numbers, they’ll show that both genders does seem to improve, but with a striking difference at baseline.

Changes in fasting insulin and fasting glucose in the Heilbronn study

Changes in fasting insulin and fasting glucose in the Heilbronn study, from baseline (white) to day 21 (eating day, gray) to day 22 (fasting day, black)

In any case, I do not think that the results from the Heilbronn study can be used to say that IF harms female glucose clearance or metabolism as such, unless a similar result can be produced a day later (dodging the transient effect) and hopefully in more health-wise comparable groups.

Summarizing the Heilbronn study, I’m 99.9% sure that the reason the men seemed to improve while the women didn’t, was because they were overall less metabolically healthy and I also think that it is very likely that the impaired glucose clearance following fasting in women is the transient post-fasting impairment described earlier.

  • CLAIM 2: That the metabolic fasting responses observed in scientific studies are not representative to women because of them using predominantly male subjects

Actually this criticism is two-pronged, with some of it related to metabolic effects of fasting and some of it related to the neuroendocrine effects of fasting.

As for the metabolic effects (as I have already discussed), IF works for women, as far as both weight loss and health biomarkers go. If you don’t believe me, please write me and I’ll help you acquire the original research articles cited previously.

As the only study that compares the metabolic responses of normal weight men and women, subjected to IF, concludes that women fares badly on IF, but does so on REALLY wobbly ground, it looks slightly like cherry picking on Stefani’s behalf claiming that IF is not appropriate for women. There is SOLID evidence that it is safe and works for pretty much all relevant health biomarkers for overweight men AND women, refuting her second claim.

  • CLAIM 3: She claims that the gender-specific neuroendocrine response (especially  increased stress and impaired reproductive health) to alternate-day fasting in rats is also applicable to humans.

With basis in several rodent studies, Stefani claims that fasting is a lot worse for females than males. Particularly, according to her, IF leads to anxiety, sleeplessness and impaired fertility. I can’t help but finding it slightly ironic that she dismisses the applicability of studies using male humans, but have no problems using rodent studies. As you may already have guessed I’m gonna question if the neuroendocrine response to fasting in rodents is representative of the response in human women.

First, I’ll be going into the part about a generalised stress response to fasting. When looking for relevant human trials, sadly there are no human studies looking into the effects of fasting on biomarkers of subjective stress. However, as amenorrhagia is considered a serious adverse effect in weight loss trials, it is rather surprising it has yet to be mentioned in any of the trials that have been published thus far. A few studies does show a bigger or earlier increase in epinephrine and cortisol in response to fasting, but not all, and certainly not to a degree, that could cause a physiological response akin to that Stefani describes in rodents. And some studies show bigger responses in males than in females – what gives? However, considering the better ability of females to mobilize fat as substrate, it would make sense for them, at least normally, to have either bigger adrenaline/epinephrine responses or enhanced sensitivity.

When going into the part about reproductive health it is somewhat easier. Rodents are known to have a more extreme responses to caloric restriction than mammals higher up the food chain. This is likely because for rodents, successfully breeding as big a litter as possible has been an important evolutionary selection criterion, and hence limited access to food would down-regulate fertility, especially in females. For humans and the other primates this is not the case, as years of nurturing is more important for producing viable offspring, than temporary limited access to food. Thus, it has actually been shown that in primates, females are less sensitive to short-term energy restriction than males (Lado-Abeal et al 2005). I’ll take the liberty of quoting from the abstract:

The changes in plasma LH and cortisol levels in fasted rhesus macaques are similar to those observed in humans and suggest that gonadotropin and corticotropin secretion are more resistant to short-term energy deprivation in female than in male primates.

In humans, it has been shown that 72 hour fasting does interact with the LH secretion during the follicular phase, but not enough to perturb follicle development or cycle length in normal-weight women (Olsen et al, 1995). However, it has also been shown that the same kind of intervention does lead to some disturbance of the menstrual cycle in lean women (BF<20) (Alvero et al, 1998). However, it can hardly come as a surprise that already lean women are more susceptible to the stressors of fasting and weight loss.

Summarizing, while I cannot refute, Stefani’s claims about anxiety and sleeplessness, I CAN say that it is unlikely that the rodent studies she’s citing reflect the human fasting condition. Also, the lack of any mention of these problems in the fasting literature (which, contrary to Stefani’s claims otherwise, does contain a lot of female subjects), reinforces this notion. As for the effects on reproductive health, I can refute her claims quite well. As long as we are not dealing with already lean women fasting for weight loss, there is little risk of perturbing the menstrual cycle. But then again, lean women should generally be wary of being in energy deficits no matter what (fasting or not).

Conclusion

Once again, I’d like to state that I’m not crusading for fasting. Actually, I’m pretty sure that it doesn’t matter that much whether you cut 25% from each meal, your number of meals/day or the number of days you eat. I have dealt as best I could with the individual points Stefani put up in her IF-criticism and this leads me to what started her out; i.e. her experiences from the PfW community. I cannot help but wonder if the fasting women she is referring to were also doing IF, Paleo and possibly even working out at the same time and thereby establishing too large energy deficits or too large diet/training metabolic stress loads and hence having bad experiences with fasting. This would seem to match better with the available evidence (and also the experiences I have made).

Also, I get the feeling that she’s pulling some kind of feministic agenda down on top of the science, (“What? are the studies mostly on men?! That must mean they’re hiding something”), however that is just speculation on my behalf. However, everyone should be able to see that it’s just silly to refute male studies, while gladly accepting them from a  different species, especially, when the applicability of this species is questionable (but I guess she didn’t know that).

Summarizing (again ;o), for non-lean women IF is a safe and tolerable approach for weight loss. The available science does not support the notion that it damages reproductive health or causes anxiety or sleeplessness. However, as with all things, certain individuals may be more susceptible to others. Also, lean women trying to get leaner are always at risk of menstrual cycle irregularities with or without fasting.

References

Alvero, R. (1998). Effects of Fasting on Neuroendocrine Function and Follicle Development in Lean Women. The Journal of clinical endocrinology and metabolism, 83(1), 76–80. doi:10.1210/jc.83.1.76

Eshghinia, S., & Mohammadzadeh, F. (2013). The effects of modified alternate-day fasting diet on weight loss and CAD risk factors in overweight and obese women. Journal of diabetes and metabolic disorders, 12(1), 4. doi:10.1186/2251-6581-12-4

Harvie, M. N., Pegington, M., Mattson, M. P., Frystyk, J., Dillon, B., Evans, G., et al. (2011). The effects of intermittent or continuous energy restriction on weight loss and metabolic disease risk markers: a randomized trial in young overweight women. International journal of obesity (2005), 35(5), 714–727. doi:10.1038/ijo.2010.171

Heilbronn, L. K., Civitarese, A. E., Bogacka, I., Smith, S. R., Hulver, M., & Ravussin, E. (2005a). Glucose tolerance and skeletal muscle gene expression in response to alternate day fasting. Obesity research, 13(3), 574–581. doi:10.1038/oby.2005.61

Heilbronn, L. K., Smith, S. R., Martin, C. K., Anton, S. D., & Ravussin, E. (2005b). Alternate-day fasting in nonobese subjects: effects on body weight, body composition, and energy metabolism. Am J Clin Nutr, 81(1), 69–73.

Horton, T. J., & Hill, J. O. (2001). Prolonged fasting significantly changes nutrient oxidation and glucose tolerance after a normal mixed meal. J Appl Physiol, 90(1), 155–163.

Hoyenga, K. B., & Hoyenga, K. T. (1982). Gender and energy balance: Sex differences in adaptations for feast and famine. Physiology & Behavior, 28(3), 545–563. doi:10.1016/0031-9384(82)90153-6

Johnson, J. B., Summer, W., Cutler, R. G., Martin, B., Hyun, D.-H., Dixit, V. D., et al. (2007). Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma. Free Radical Biology and Medicine, 42(5), 665–674. doi:10.1016/j.freeradbiomed.2006.12.005

Klempel, M. C., Kroeger, C. M., & Varady, K. A. (2013). Alternate day fasting (ADF) with a high-fat diet produces similar weight loss and cardio-protection as ADF with a low-fat diet. Metabolism: clinical and experimental, 62(1), 137–143. doi:10.1016/j.metabol.2012.07.002

Klempel, M. C., Kroeger, C. M., Bhutani, S., Trepanowski, J. F., & Varady, K. A. (2012). Intermittent fasting combined with calorie restriction is effective for weight loss and cardio-protection in obese women. Nutrition Journal, 11, 98. doi:10.1186/1475-2891-11-98

Kumar, S., & Kaur, G. (2013). Intermittent fasting dietary restriction regimen negatively influences reproduction in young rats: a study of hypothalamo-hypophysial-gonadal axis. PloS one, 8(1), e52416. doi:10.1371/journal.pone.0052416

Lado-Abeal, J., Robert-McComb, J. J., Qian, X.-P., Leproult, R., Van Cauter, E., & Norman, R. L. (2005). Sex differences in the neuroendocrine response to short-term fasting in rhesus macaques. Alternate day calorie restriction improves clinical findings and reduces markers of oxidative stress and inflammation in overweight adults with moderate asthma, 17(7), 435–444. doi:10.1111/j.1365-2826.2005.01323.x

MERIMEE, T. J., & FINEBERG, S. E. (1973). Homeostasis During Fasting. II. Hormone Substrate Differences Between Men and Women. The Journal of clinical endocrinology and metabolism, 37(5), 698–702. doi:10.1210/jcem-37-5-698

MERIMEE, T. J., MISBIN, R. I., & PULKKINEN, A. J. (1978). Sex Variations in Free Fatty Acids and Ketones during Fasting: Evidence for a Role of Glucagon. The Journal of clinical endocrinology and metabolism, 46(3), 414–419. doi:10.1210/jcem-46-3-414

Mittendorfer, B., Horowitz, J. F., & Klein, S. (2001). Gender differences in lipid and glucose kinetics during short-term fasting. American journal of physiology Endocrinology and metabolism, 281(6), E1333–E1339.

Olson, B. R. (1995). Short-term fasting affects luteinizing hormone secretory dynamics but not reproductive function in normal-weight sedentary women. The Journal of clinical endocrinology and metabolism, 80(4), 1187–1193. doi:10.1210/jc.80.4.1187

Runcie, J., & Hilditch, T. E. (1974). Energy provision, tissue utilization, and weight loss in prolonged starvation. British medical journal, 2(5915), 352–356.

Soeters, M. R., Lammers, N. M., Dubbelhuis, P. F., Ackermans, M., Jonkers-Schuitema, C. F., Fliers, E., et al. (2009). Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism. Am J Clin Nutr, 90(5), 1244–1251. doi:10.3945/ajcn.2008.27327

Soeters, M. R., Sauerwein, H. P., Groener, J. E., Aerts, J. M., Ackermans, M. T., Glatz, J. F. C., et al. (2007). Gender-Related Differences in the Metabolic Response to Fasting. The Journal of clinical endocrinology and metabolism, 92(9), 3646–3652. doi:10.1210/jc.2007-0552

Varady, K. A., Bhutani, S., Church, E. C., & Klempel, M. C. (2009). Short-term modified alternate-day fasting: a novel dietary strategy for weight loss and cardioprotection in obese adults. American Journal of Clinical Nutrition, 90(5), 1138–1143. doi:10.3945/ajcn.2009.28380

Varady, K. A., Bhutani, S., Klempel, M. C., & Lamarche, B. (2010). Improvements in LDL particle size and distribution by short-term alternate day modified fasting in obese adults. The British journal of nutrition, 105(04), 580–583. doi:10.1017/S0007114510003788

Varady, K. A., Bhutani, S., Klempel, M. C., & Kroeger, C. M. (2011). Comparison of effects of diet versus exercise weight loss regimens on LDL and HDL particle size in obese adults. Lipids in Health and Disease, 10, 119. doi:10.1186/1476-511X-10-119

Walford, R. L., Mock, D., Verdery, R., & MacCallum, T. (2002). Calorie restriction in biosphere 2: alterations in physiologic, hematologic, hormonal, and biochemical parameters in humans restricted for a 2-year period. The journals of gerontology Series A, Biological sciences and medical sciences, 57(6), B211–24.

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