Does stress cause infertility?
Dr Adam Massey discusses a new study taking place at CARE
It is one of the most commonly asked questions by patients facing fertility difficulties - ‘can stress affect my fertility’? The purpose of this blog is to share with you an overview of the evidence for the role of stress on fertility outcomes. It also introduces our most recent research in this area examining the role of the ‘stress hormone’ cortisol on IVF outcomes. This overview is not exhaustive but I hope it will give you a flavour of the state of play in this area of work.
What is stress?
Stress is something that affects us all at times throughout our lives and comes in many different forms in our hectic modern world. However, while the term ‘stress’ is now an everyday term that we all use it is often not very well defined.
What do we actually mean when we are feeling ‘stressed’? There are many definitions of what stress is and what one-person finds stressful another individual may not. However, in general terms, ‘stress’ is best defined as a pattern of physiological, behavioural and cognitive responses to real or imagined stimuli (called ‘stressors’) that an individual perceives as threatening a goal or their wellbeing. Stress can be short-lived or long lasting. Acute stressors are short term often stemming from demands and pressures of the recent past or anticipated demands of the near future e.g., conducting a public speaking task or sitting in heavy traffic on the way to work.
Chronic stressors are characterised by more long term strain e.g., suffering from bereavement or facing a health condition such as fertility difficulties. Research indicates that somewhat transient shorter-lived stress may actually be good for us e.g., heightening our cognitive awareness and mobilising energy to prepare us for ‘fight or flight’. However, stress that is more chronic and longer lasting can result in physiological wear and tear referred to as ‘allostatic load’ and may have deleterious affects on our health.
What happens when we are stressed?
There are two systems that are central to the human stress response. These systems are known as the autonomic nervous system and the hypothalamic pituitary adrenal (HPA) axis. These two systems play a crucial role in how our bodies respond to acute and chronic forms of stress.
The sympathetic and parasympathetic nervous systems are distinct parts of the autonomic nervous system. Both branches play key roles in our immediate response to acute stress. The sympathetic system is responsible for preparing our body for action (i.e., fight or flight) when we perceive a stressor. Upon perceiving a stressor, several immediate responses occur within the body that are driven by the sympathetic system including dilation of pupils, increases in heart rate, opening of the arteries throughout working muscles, constriction of arteries for non- working muscles, slowing of digestion and other functions that are not immediately needed. The overall purpose of this cascade of events is to provide enough energy to deal with perceived danger. Once the stressor subsides, the parasympathetic branch of the autonomic nervous system restores the body to normal functions.
The HPA axis is a somewhat second stage system, which comes into action at a slower place than the sympathetic nervous system and serves to provide additional energy resources. The HPA axis is geared to deal with chronic more long lasting sources of stress. The HPA axis is closely connected with the functioning of the immune and reproductive system and this is why it has become the focus of considerable research interest. One of the main by-products of the HPA axis is the ‘stress hormone’ cortisol, which I will discuss a little later in this blog.
Stress and Fertility
For several decades there has been considerable debate regarding whether or not stress may affect fertility. Much of this work has been conducted in the context of IVF because it allows researchers to collect data on pregnancy outcomes within a relatively short period (6-8 weeks). While we have made great progress in this area the sentiment we are faced with is that there is still considerable uncertainty regarding whether or not stress is a determining factor. On one hand some argue that stress is a result of experiencing fertility difficulties but has no bearing on fertility per se. Whereas, on the other hand, other researchers argue that stress is capable of perturbing reproductive function and may contribute to fertility difficulties. Much of the uncertainty patients face regarding whether or not stress influences fertility lies in the fact that we as scientists have not yet been able to provide a conclusive answer to this question.
To illustrate this point, two meta analyses were published in 2011 by two expert research groups on the role of stress on IVF outcomes. Both meta analyses were high quality collating the evidence for the role of emotional distress on IVF. However, in doing so both meta analyses came to very different conclusions. Boivin et al., (2011) conducted a meta analysis of 14 studies (3583 patients) and concluded that ‘emotional distress will not compromise chances of becoming pregnant’. However, in contrast, Mathiesen et al., (2011) meta analysis included 31 studies (4902 patients) and concluded that ‘small but significant associations were found between stress, anxiety and pregnancy’. There are several reasons why these reviews may have yielded different findings. For example, how stress was defined by the researchers and the kinds of studies included. However, a limitation of both reviews is that they only report findings from studies that assessed self reported stress. Self-reporting involves asking patients how they are feeling using a questionnaire.
While this is a common method used within psychological research, measuring stress in this way is inherently imprecise. For example, using only self reported measures introduces issues such as ‘recall bias’ (i.e., patients may recall how they are feeling differently after the event) and often how we feel may not necessarily be how our body is responding. Therefore, in an attempt to more objectively quantify stress and better explain the biological mechanisms involved in the stress>fertility relationship there has been a growing interest in the role of the ‘stress hormone’ cortisol.
Cortisol and Fertility
Cortisol is a glucocorticoid hormone often coined the ‘biomarker of stress’. Cortisol is secreted from the hypothalamus pituitary adrenal (HPA) axis, which is central to the body’s stress response. Cortisol plays functional roles throughout the body in regulating metabolism, blood pressure and reproductive functions. However, many decades of research have demonstrated that the HPA axis is highly responsive to stress and that elevated cortisol levels resulting from stress can have negative effects on a range of health outcomes. In 2014, Massey et al., conducted a systematic review of 25 year’s worth of research (>1600 patients) exploring the role of cortisol on a range of IVF outcomes. The authors identified 12 studies that had examined the affects of cortisol on pregnancy. This review showed that evidence for cortisol was mixed. For example, three studies found that elevated cortisol increased the likelihood of pregnancy. Four studies showed that high cortisol decreased the likelihood of pregnancy. Whereas, five studies failed to find any significant associations between cortisol and pregnancy at all. There are several reasons why evidence for the role of cortisol on fertility has been mixed.
First, the majority of studies failed to control for variables which are known to influence cortisol levels (e.g., time of day – which is important because cortisol follows a diurnal cycle) so comparisons are difficult to make between studies. Second, studies measured cortisol at different stages of treatment. Whilst IVF is a useful clinical model for exploring the effects of stress on reproductive outcomes, over half of the studies (7/12) measured cortisol following gonadotrophin administration. Gonadotrophins have profound effects on the HPA axis and, therefore, are likely to have confounded any observed associations between HPA function and pregnancy. Third, a major limitation of previous studies is that researchers had only assessed short term ‘acute’ levels of cortisol such as saliva, blood or urine. A problem with these methods is that they only provide a ‘snapshot’ of hormonal function at a given time over short durations of minutes to hours. However, cortisol is pulsatile which means that, like blood pressure, it is forever changing. The difficulty that researchers face, therefore, is that in order to provide an accurate measure of cortisol, between 3 and 9 samples would be needed throughout the day over a number of days in order to assess cortisol with any degree of accuracy.
However, a relatively new technique for assessing long-term cortisol levels may provide great promise for assessing the effects of cortisol on fertility and quantifying the role of stress on health. Hair sampling enables researchers to assess cumulative long-term cortisol levels over periods of up to 6 months with a single non-invasive sample.
In 2016, a study by Massey et al., found that elevated levels of cortisol measured in hair were associated with a reduced likelihood of pregnancy (accounting for up to 27% of the variance). These findings suggest that interventions to lower cortisol prior to embarking on IVF may improve chances of treatment success.
Our latest Research
The University of Nottingham are now collaborating with CARE Fertility Nottingham to further explore the link between cortisol and pregnancy. As part of this study we are recruiting 200 women undergoing IVF.
There are two broad objectives we look to achieve when conducting research in this area. The first objective is to improve the quality of treatment that every patient receives. To this end, being able to quantify stress by assessing cortisol may enable doctors to make suitable provision for patients that are in most need of support. Our second objective is to maximise patients’ chances of IVF success. To this end, our research may lead to a number of lifestyle interventions that target factors known to influence cortisol levels with a view to optimising the likelihood of pregnancy.
As part of this study, we will be conducting a comprehensive assessment of a range of lifestyle factors that are associated with cortisol levels. The hope is that by conducting this study we can provide more solid evidence for the affects of stress (and other known factors that influence cortisol) on pregnancy outcomes in women undergoing IVF.
I hope you have found this blog interesting and thank you to all the patients who have taken the time to take part in our research so far.