While I was doing research for the previous article in this series on IF, I had a conversation with one of our coaches, Elle. Elle mentioned that she had come across some material online discussing the potentially negative impact IF can have on women’s hormones. Did I know anything about this, she asked? I had to admit that, no, I didn’t really know anything about it. I had heard mutterings of this sort before but to my discredit I’ve never really looked into it. Honestly, my intuition was always that 14-16 hours of fasting is unlikely to cause any deleterious effects in women since it’s a fairly moderate protocol. Intuition is overrated, however, and we’re about science and data here. So I decided to get stuck into the literature to see what I could find on women and IF. What does the evidence say?
Before I proceed, I want you to make me one promise: please read this article in full; because if you read just half of it, you won’t understand the full picture and I don’t want you coming away with an unbalanced view on this important topic. If you read just half of this article, you may leave with the impression that women should avoid IF at any cost. This isn’t the case at all. I absolutely think that IF is a viable and potentially effective strategy for women. But there may be some additional considerations you should be aware of and there may be some adjustments to optimise your approach.
The biology of scarcity
Let’s start with some theory. What is the potential biological basis for women responding differently to intermittent fasting? Animals, like businesses, are confronted by the fundamental problem of resource scarcity. Life involves a number of resource-intensive processes and there is not always enough energy available to perform all of them at the same time. We’re thinking of the basic stuff here: survival, reproduction, growth, maintenance etc. This is why, for example, animals normally grow and only then reach reproductive maturity. There simply isn’t enough energy to grow and reproduce at the same time. An Animal’s biology has to make sophisticated decisions concerning where best to expend its available energy.
Figure: relationship between reproductive rate and longevity of animals. Higher reproductive effort yields lower survival rates; lower reproductive effort yields higher survival rates. The relationship is not linear.
In contemporary times, we don’t face a huge amount of scarcity. We all know there’s plenty of energy around, in the form of junk food and fizzy drinks. But, when we undergo fasting we impose an artificial energy constraint on ourselves. Fasting is a mild stressor, and that is part of the reason why it may promote health and longevity: stressors induce stress responses which can render you more resilient in the future.
But men and women may respond differently to the same scarcity of energy. As Martin et al. point out in a paper from 2007 published in Endocrinology:
“Females and males typically play different roles in survival of the species and would be expected to respond differently to food scarcity or excess’
Evolutionarily, the role of the female in reproduction is more energy-intense. While males often simply supply sperm, females must carry the foetus to term. Females are also generally responsible for the care of their young and for producing milk (in mammals at any rate!). All of these things are incredibly resource-intensive. For that reason, when faced with food scarcity and a decision to allocate limited energy to either survival or reproduction, we might expect females to shift further away from reproductive functions and more towards survival strategies. Reproduction is so demanding of energy for females that even a moderate scarcity could mean that it’s off the cards.
The stress-response and reproductive cycle in rodent models
So that’s the theoretical basis for a difference between men and women when it comes to IF. But to what extent is this borne out in the research? Do we really see the predicted sex-difference? And do normal IF protocols impose sufficient scarcity to induce these responses?
One thing is for sure: we certainly do see these differential effects in studies carried out in rats. We will discuss the extent to which this is, or is not, relevant shortly. But at the very least, the rat data gives us a sense of the mechanisms involved.
Martin et al. found that when rats were maintained on an alternate-day fasting protocol for 6 months, males and females responded significantly differently. Corticosterone (the rodent equivalent of cortisol) levels rose significantly in female rats while it actually dropped slightly in males, indicating that the fasting protocol caused a greater stress-response in females than in males.
Figure: corticosterone levels in control (C) and intermittent fasted (IF) rodents. Males on the left panel, females on the right panel.
Adding further weight to this observation, female rats responded to IF with increased measures of cognitive performance and physical activity. Females kept on IF were more than twice as active as control rats in the day-time. Plasma levels of brain-derived neurotrophic factor (BDNF) increased in females while levels in males fell. BDNF stimulates the growth of new neurons and synapses and so rising levels mean higher potential levels of cognition. These two effects imply that female rats had activated survival mechanisms to a greater extent than male rats in response to food restriction. In times of potentially life-threatening food-scarcity, animals adapt by increasing mental capacity in order to more effectively find food and by upping movement in order to increase the area over which they can hunt or gather.
Figure: plasma brain-derived neurotrophic factor (BDNF) in male (left) and female (right) rats in control (C) and alternate day fasting (IF)
Figure: ambulatory activity levels of rats
This shift in physiology, towards survival mechanisms, becomes even clearer when you consider what happens to the rats’ reproductive functions. Martin et al. found that the oestrous cycle was disrupted in 42% of female rats on IF (the estrous cycle is the rodent equivalent of the menstrual cycle). A second paper, published by Kumar et al., specifically studied the relationship between IF and reproductive function in female rats. Their findings corroborate Martin et al.’s data and add more detail. How is the reproductive cycle disrupted by IF?
IF and the HPG axis in female rats
The hormonal system that regulates the reproductive cycle is the hypothalamic-pituitary-gonadal axis (HPG axis for short). The hypothalamus releases gonadotropin-releasing hormone (GnRH) which travels to the anterior pituitary gland to stimulate the release of luteinising hormone (LH) and follicle stimulating hormone (FSH). These hormones act on the ovaries to coordinate the development of the follicle and ovulation.
Figure: the hypothalamic-pituitary-gonadal (HPG) axis in females
Kumar et al. also compared rats maintained on alternate day fasting against ad libitum fed rats. Their findings confirm that this fasting protocol disrupts (and in many cases halts) the estrous cycle. But how does this happen?
The first observation is that serum luteinising hormone (LH) levels were much lower in IF rats than in control rats. It is a surge in LH levels in the estrous (or menstrual) cycle that brings about ovulation, the release of the egg from the follicle. Therefore, chronically low levels of LH prevent this crucial step in the reproductive cycle.
Figure: serum luteinising hormone (LH) levels in ad-libitum (AL) and alternate-day fasted (DR) rats
Looking up-stream of this effect, Kumar et al. measured that female oestradiol (one of the forms of oestrogen) levels were markedly higher in female IF rats than in the control group. In the complex cascade of the estrous cycle, oestradiol inhibits the release of GnRH from the hypothalamus, thereby reducing LH release from the pituitary gland (see the figure above).
Figure: LH in rats fed ad-libitum (AL) and on alternate-day fasting (DR)
Figure: estradiol (a form of oestrogen) levels in ad-lib (AL) and alternate-day fasted (DR) female rats
Leptin levels may be one of the mechanisms through which energy-scarcity is communicated to the HPG axis. Low leptin levels, as observed in IF female rats, are signals of low energy status. Leptin can inhibit the release of GnRH from the hypothalamus by reducing the expression of an important neuropeptide, kisspeptin. All together then, hormone levels in female IF rats do suggest that fasting is having a negative effect on reproductive health.
Figure: leptin levels in ad-lib (AL) and alternate-day fasted (DR) rats. Also compares pro-estrous (PRO) and diestrous (DIE) female rats.
The problems with rodent data
Ok, sorry. I realise that’s a lot of nerdiness and probably too much detail. But what should we make of this data?
There are some significant limitations to the relevance of these findings for women undergoing standard IF protocols. First of all, rats are a potentially misleading surrogate for human data in this field. Rats have a metabolic rate 7 times faster than humans. Coupling this with the fact that both studies used alternate day fasting means that these observations are valid only for extreme fasting protocols. If you are fasting for just 16 hours a day, what is observed in rats that fast every other day may not be relevant at all. We are comparing a very moderate with a pretty brutal fasting system. It’s worth noting that the rats in the Kumar et al. study were just 3-4 months old while most studies equate 6 month-old rats to 18 year-old humans. In other words, the rats being studied were in their late adolescence and for this reason may be less relevant for older adults.
That being said, there is limited human data on women and IF which suggest that some of the effects observed in rodents may be applicable. Heilbronn et al. placed women on an alternate-day fasting schedule for 22 days and observed that their glucose response to a test-meal was impaired, while the glucose response in men was unchanged. Research shows that elevated levels of cortisol can disrupt glucose metabolism. This paper did not measure the hormone but it’s possible that this glucose dysregulation is suggestive of an upstream stress-response mediated by cortisol, as was observed in the rats.
Figure: glucose (A) ad insulin (B) response to a test meal before and after 22 days of alternate day fasting in men and women. Statistically significant differences are highlighted with: *
I have some reservations about this study since did not have a control group and, again, used the alternate-day approach to IF. The study was also short, had few participants and did not supervise food intake. I’d like to see a better controlled study, which measures cortisol, to confirm these results but there may be something there.
Practical advice for women doing IF
I think the rat studies provide a useful framework for anyone undertaking, or thinking of undertaking IF. It can’t hurt to be mindful of the risks, even if they might be very minimal. A woman doing any kind of IF should pay attention to:
The menstrual cycle – Any disruption to the regularity of your cycle (in the absence of other obvious stressors) could indicate the IF is not right for your physiology.
Sex hormones – Measure these every 3-6 months depending on how demanding an IF protocol you are adhering to. Pay particular attention to LH and oestradiol. If LH is too low and oestradiol too high (for the relevant point in your cycle), consider switching to a less extreme protocol.
Cortisol – Again measure this every 3-6 months. If your fasting cortisol is very elevated, confirm the result with a 24 hour urine test to make sure the observation is real. Then consider switching your IF plan.
Women might also want to start with less extreme version of IF. Perhaps start with a 12 hour fast. See how you feel. If you feel ok after 3-4 weeks, progress to 13 and 14 hour fasts. I think most of the benefits of IF can be obtained with 14 hour fasts in any case, so there is no real need to push much past that.
In conclusion, there is some evidence to suggest that the more demanding IF schedules may be deleterious to women’s cortisol levels, glucose metabolism and reproductive systems. Extreme caloric restriction can lead to disruption of reproductive cycles through a cascade of effects: lower leptin and higher oestradiol leading to inhibited GnRH release and decreased LH levels. Fasting may also lead to hypercotisolaemia through a more pronounced stress response. However, the evidence is mostly based on rodent models and alternate-day fasting systems. Human data is limited and flawed. More controlled trials would certainly be needed to confirm a real risk in women undergoing normal IF protocols. It’s always sensible to be mindful of risks though. So I recommend that women consider starting with more moderate approaches and keep an eye on levels of key hormones: LH, oestradiol and cortisol; much the way men may want to keep an eye on testosterone and IGF-1. I don’t think there is anything in the literature to suggest that women should avoid IF and I believe it will still be a great approach in most cases. But, as with everything, n=1. We are all individuals and it is up to you to figure out the best approach for yourself.