Tag Archives: physiology

The female athlete: A balancing act between success and health

By Jessica Piasecki, Manchester Metropolitan University, UK, @JessCoulson90

A longer version of this article originally appeared in Physiology News.

There is a very fine line between training, competition, and recovery for the elite athletes (1). For female athletes, they have an extra balance to take into consideration: the menstrual cycle.

The monthly cycles

The menstrual cycle is a natural process and is essential to maintain bone health and fertility. It can start from the age of 12 and continues until the onset of menopause around the age of 49-52.

The cycle occurs over a period of 28 days. The first 14 days are known as the follicular phase. During this phase, around day 10, the hormones oestrogen, LH (luteinizing hormone) and FSH (follicular stimulating hormone) rise, reaching their peak around day 14.

LH reaches a level double than that of both oestrogen and FSH. After day 14 LH levels rapidly drop off while oestrogen and FSH fall off more slowly, over a 5 day period. The second 14 days are known as the luteal phase and there is a gradual increase in another hormone, progesterone, which reaches a peak around day 22 and returns to base levels at day 28.


Bone stability and structure

Of these three hormones, oestrogen is a key regulator of bone resorption, without oestrogen there would be an excess of bone being broken down over new bone being formed. Bone is in a state of constant turnover, with the help of two types of bone cells (osteoblasts and osteoclasts). Osteoblasts are involved in bone formation, while osteoclasts are involved in bone resorption.

Bone resorption occurs at a much higher rate than formation; bone resorption takes just 30 days whereas the bone remodelling cycle takes 4 months. Therefore, a slight imbalance can lead to a bone fracture very quickly (2).

More is not always better

Elite female athletes, particularly those involved in sports that usually adopt a leaner physique with low body fat, are at a greater risk of disordered eating. The reasons for this disordered eating could be external pressures from teams, coaches and sponsors, or the athletes themselves having the belief that the leaner and lighter they are, the quicker they will be. These pressures may also cause the athlete to push their body to further extremes.


Without the necessary energy intake, the menstrual cycle will most likely become irregular and eventually cease (which is known as amenorrhea). Amenorrhea causes the levels of oestrogen to become reduced, leaving a disproportionate ratio of osteoblasts and osteoclasts, and a higher rate of bone resorption.

This may ultimately lead to bone injuries, (the precursor to osteoporosis), or even osteoporosis at a very young age, making any further career achievements even more difficult.

These three symptoms (disordered eating, amenorrhea and osteoporosis) became more prevalent in the 1990s and were termed ‘The Female Athlete Triad’ in 1997 by the American College of Sports Medicine. It has been estimated that only 50% of trained physicians are knowledgeable about the female athlete triad (3). More recently the triad has been regrouped within a term known as RED-S (Relative energy deficient syndrome); deemed to result from continual disordered eating. Being in a state of energy deficiency for a long duration can disrupt many processes within the body, including the cardiovascular, digestive and hormonal . Redefining the RED-S also allows male athletes who present with similar issues to be included (4).

Current research has looked at the differing effects of the components of the triad on injuries, and bone and muscle health. At Manchester Metropolitan University, we have carried out our own research on some of the UK’s most renowned female endurance runners, investigating the effects of altered menstrual cycle on bone health. Athletes with amenorrhea presented with a greater endocortical circumference (the outer circumference of the inner cortical bone in the tibia (lower leg) and radius (forearm) than controls. Only the athletes with regular menstrual cycles (eumenorrheic) had a greater cortical area, in the tibia and radius, compared to controls. The athletes with amenorrhea had thinner bones (i.e. larger but not denser). We are working to better understand the issues, so accurate diagnosis will become more frequent.

What we really need is education at a young age, as most athletes become familiar with the triad only once they have been diagnosed with a bone injury. If athletes are made aware of the symptoms and issues around the triad before they occur, then nutrition and menstrual cycles can be more closely monitored as they progress through their athletic careers.

Read the full-length version of this article in our magazine, Physiology News.


  1. Barnett, A (2006). Using recovery modalities between training sessions in elite athletes does it help? Sports Med (36), 781-96
  2. Agerbaek, M. O., Eriksen, E. F., Kragstrup, J., Mosekilde, L. and Melsen, F. (1991) A reconstruction of the remodelling cycle in normal human cortical iliac bone. Bone Miner, 12 (2), pp. 101-12.
  3. Curry, E, Logan, C, Ackerman, K, McInnia K, Matzkin, E (2015) Female athlete triad awareness among multispecialty Physicians. Sports Med Open. 1:38.
  4. Tenforde, AS, Parziale, A, Popp, K, Ackerman, K. (2017) Low Bone mineral density in male athletes is associated with bone stress injuries at anatomic sites with greater trabecular composition. Am J Sports Med. DOI: 10.1177/0363546517730584

Tight squeeze: a new way to get larger drugs into the brain

by Michelle Pizzo & Robert Thorne, University of Wisconsin Madison, USA

The brain and spinal cord are a difficult body parts to fix. Only seven percent of drugs for diseases of the brain and spinal cord succeed, whereas fifteen percent of drugs for other parts of the body do (1). New research published in The Journal of Physiology may have found part of the solution: a method for getting bigger drugs into the brain.

The issue is, in part, that we still lack a detailed understanding of the complicated structure and physiology of the brain’s cells and fluids, including the communication between the cells and fluids (2). This limited knowledge has further compromised our understanding of the delivery and distribution of drugs in the central nervous system (brain and spinal cord, abbreviated as CNS), particularly for large-molecule drugs (bigger than about one nanometer) which are unable to cross the blood-brain barrier to reach the brain tissue.

A tight fit: getting big antibody drugs into tiny brain spaces

Among the best examples of promising large-molecule therapeutics are antibodies, the weapons of our immune system. They work by recognizing a part of a molecule (called an antigen). Indeed, five of the top ten drugs by revenue are antibodies (3).

Besides being great potential drugs, antibodies are very abundant in the fluid that bathes the brain and spinal cord (called cerebrospinal fluid, or CSF) (4). Antibodies in the CSF may play an important role in the brain’s immune system and contribute to central nervous system autoimmune disorders (like multiple sclerosis) that cause our immune system to attack our own body.

Because antibodies (and other large-molecule protein therapeutics) are 10 times the size of small-molecule drugs, it has long been thought that their distribution in the brain will in most cases be much more limited than small-molecule drugs (5).

However, a recent study published in The Journal of Physiology from the University of Wisconsin-Madison by Michelle Pizzo, Robert Thorne, and their colleagues (6) has uncovered an unappreciated key mechanism governing antibody transport within the CNS that may ultimately allow these big proteins to access much more of the brain from the CSF than previously thought.

This has important implications as there are numerous clinical trials that are ongoing in the United States for treatment of brain cancers with antibody drugs.

Go with the flow: using the fluids of the brain for antibody drug delivery

Injecting antibodies of two different sizes into the CSF of rodents, the researchers found two main mechanisms of transport—1) slower movement (called diffusion) in between the tightly packed brain cells, and 2) quicker transport along tubular spaces around blood vessels, (called perivascular spaces) (6).

As expected, they found that the slower movement of these large molecules by diffusion was quite limited, whereas the smaller antibodies penetrated further. Aspects of the quicker transport around the blood vessels appeared to be independent of size; both the smaller and larger antibodies could reach deep into the brain along the walls of blood vessels in a short amount of time.

This is great news for the CSF delivery of biotherapeutics, including protein drugs like antibodies. The quicker perivascular flow along these tubular pathways is thought to exist in humans, so such flows are likely translatable/scalable to the clinic. Slower, diffusive transport, on the other hand, does not scale across species. In other words, if effective drug diffusion is limited to a distance of one mm in the rat brain, it will also be limited to one mm in the much larger human brain. This distance may not be enough to treat most brain diseases.


A large, full-size antibody protein (green) infused into the fluid bathing the brain (cerebrospinal fluid) reaches deep into the brain along the spaces around blood vessels (red). Nuclei of all the brain/blood vessel cells are labeled in blue. (Photo credit: Michelle Pizzo)

They also found that the smaller antibody was able to get into more of these tubular perivascular spaces compared to the larger antibody, which meant a significantly poorer overall delivery was obtained for these full-sized antibodies. Two questions arose from this finding—1) what barrier is causing this size-dependent entry into the perivascular space, and 2) can the barrier be altered to improve delivery?

Let me in: identification of a new barrier between the CSF and brain and a strategy to open it

Pizzo and her colleagues found that a layer of cells wrapping around blood vessels on the surface of the brain, between the CSF and the perivascular spaces, is a likely candidate for the size-dependent barrier.

They suggested that pores or openings in these cells may contribute to a sieving effect, allowing smaller molecules into the perivascular space but making entry more difficult for larger molecules. A method that has previously been used to open cell barriers is to administer a hyperosmolar (which more or less means, concentrated) solution that makes these cells give up their water to dilute the surrounding solution. Thus the water exits the cells (by osmosis) and causes them to shrink, allowing gaps between cells and pores in the cells to open. Pizzo and colleagues then reasoned that if they were to administer this solution into the CSF, the larger antibodies would enter the perivascular spaces better.

This is essentially what they found; the larger antibody had significantly greater access (about 50%) to the perivascular spaces when it was delivered into the CSF with a hyperosmolar solution.

Numerous studies of protein drugs administered into the CSF are ongoing for brain cancer and childhood metabolic diseases that affect the brain (called neuropathic lysosomal storage disorders). Thus, an improved understanding of how these large molecules move through the brain is critical.

This new research has shed light on how these antibodies use different types of transport to move between the CSF and the brain in rodents, revealing that fast perivascular transport can reach deep into the brain and may offer the best hope for translation to humans.

Even more exciting is their new hypothesis for the cellular barrier that may regulate entry into these perivascular spaces. Manipulating this ‘barrier’ could lead to improved methods for delivery of drugs to the brain and spinal cord.


  1. Pangalos MN, Schechter LE, Hurko O (2007) Drug development for CNS disorders: strategies for balancing risk and reducing attrition. Nat Rev Drug Discov 6(7):521–32.
  2. Thorne RG (2014) Primer on Central Nervous System Structure/Function and the Vasculature, Ventricular System, and Fluids of the BRain. Drug Delivery to the Brain: Physiological Concepts, Methodologies, and Approaches, eds Hammarlund-Udenaes M, de Lange E, Thorne RG (Springer-Verlag, New York), pp 685–707.
  3. Lindsley CW (2015) 2014 global prescription medication statistics: strong growth and CNS well represented. ACS Chem Neurosci 6(4):505–506.
  4. Davson H, Segal MB (1996) Physiology of the CSF and blood-brain barriers (CRC Press).
  5. Wolak DJ, Thorne RG (2013) Diffusion of macromolecules in the brain: implications for drug delivery. Mol Pharm 10(5):1492–504.
  6. Pizzo M, et al. (2017) Intrathecal antibody distribution in the rat brain: surface diffusion, perivascular transport, and osmotic enhancement of delivery. J Physiol:Accepted manuscript.

Exercise, stress and Star Wars: Best of 2017 roundup

Happy New Year! In 2018, we look forward to more physiology fun, and to giving you an insight into the exciting new developments in the Science of Life!

Physio-what, you ask? Take a look at our animation below introducing physiology! Scroll down to find out more about a centuries-old shark patrolling the deep Arctic Ocean, how being active gives children’s hearts a head start for life, and why it’s time scientists took back control from exercise gurus, in our best of 2017 roundup!

1. Exercise scientists should fight the exercise gurus

Social media apps - With new Google logo

Exercise gurus build strong rapports with their audience to encourage commitment, but they will often simplify a large body of scientific evidence to back up their advice.

In this post, Gladys Onambele-Pearson and Kostas Tsintzas discuss the risks of letting exercise gurus disseminate exercise science to the public, and why it may be time for scientists to become the actual celebrities.

2. The Myth of a Sport Scientist


There is a mismatch between the perceptions and reality of what a sport scientist is and what skills this career entails: just because exercise scientists use models of sport performance, exercise bouts or physical activity sessions, doesn’t mean that there aren’t complex scientific skills, theories, analytics and techniques behind the work.

Read more from sport scientist Hannah Moir in this post.

3. Shark Diary, Episode I: On the trails of the Greenland shark


How do you keep lab chemicals cool when there’s no fridge in your room? Well, if you’re in chilly Denmark, you could just hang them outside your window.

Holly Shiels did just that in Copenhagen, on her way to Greenland to join a team of physiologists on a shark research mission. Their aim was to gather data on the physiology of the Greenland shark. Clarifying how these animals reach hundreds of years of age without developing diseases associated with human ageing, like cancer and heart disease, could lead to new therapies down the line, and understanding shark physiology is also important for their conservation.

Read more about the mission in this post, and check out watch below to see the researchers braving the icy waters of the North Atlantic and releasing a tagged Greenland shark.

4. Breath of the Sith: a case study on respiratory failure in a galaxy far, far away


Have you always wondered what actually is going on behind the mask? Darth Vader’s acute respiratory failure appears to be the consequence of a number of factors, including direct thermal injury to the airways, chemical damage to the lung parenchyma caused by inhalation of smoke and volcanic dust particles, carbon monoxide poisoning, as well as secondary effects to his severe third degree burns, which seems to cover ~100 % of his total body surface area.

Read on as Ronan Berg and Ronni Plovsing make a tongue-in-cheek diagnosis of the numerous respiratory ailments of everyone’s favourite Sith Lord.

5. Exercise now, thank yourself later


Exercise is good for the heart, but the benefits fade soon after we stop training… or so we thought. Studies so far have focused on adults, but research published last November in The Journal of Physiology reveals that exercise in early life could have lifelong benefits for heart health.

This is because young hearts are able to create new heart muscle cells in response to exercise, an ability that is mostly lost in adulthood. Glenn Wadley, Associate Professor at Deakin University and author of the study, explains the findings in this post, and makes the case for children to get active!

As if that wasn’t enough reason to exercise, being active is one of three tips that can help relieve the stress we feel for instance at the approach of exams. Watch our animation below to find out more about what stress does to our bodies, and start making good on those New Year resolutions!

Careers – no ‘one size fits all’ for scientists

A longer version of this article originally appeared in Physiology News.

‘What matters most is how well you walk through the fire’ – Charles Bukowski

The career path of scientists is oft the result of happenstance; a chance meeting at a conference, a quirk in a dataset, a change in personal circumstance. There’s no one size fits all for scientists’ careers. We sought to highlight this with several case studies to encourage you on your way.

The beauty of science is it takes you across borders
by Rebecca Dumbell, Postdoctoral Training Fellow, MRC Harwell Institute, UK

I completed my PhD from the Rowett Institute of Nutrition and Health, University of Aberdeen in 2014. The Rowett had merged with the University a few years before I joined, and combined with the rural location at the time, this meant that it still had the feel of a research institute. Towards the end of my PhD I heard about a postdoc position coming up at the University of Lübeck in Germany through word of mouth. In a bit of a whirlwind I flew out to Germany for my interview the day after submitting my thesis, and I started the job a few months later.

Getting set up in my new job and new country was a challenge. I quickly learned that I needed a lot of documents, all from different offices located very far from each other, and they all had to be collected in a particular order. My EU passport smoothed the process and made my experience much easier than what I witnessed my non-EU colleagues go through. Within 1 week I had everything I needed, including a place to live, a bank account, health insurance and a pension plan.


Lübeck. / Shutterstock

I spent almost 2 years as a postdoc in Lübeck and I really loved living in Germany. Half of my colleagues were German and the rest came from all over the world, all speaking English in the lab. This was a lot of fun and we set up things like ‘international cooking club’ and, my personal favourite, whisky club. I found that as the only native English speaker I was the go-to proofreader; this certainly improved my grammar if not the work I was checking!

I now work at the MRC Harwell Institute in Oxfordshire as a Postdoctoral Training Fellow, and again find myself in a research institute in a rural setting. This comes with its own advantages and challenges. I have to go out of my way to build on my undergraduate teaching experience. But, once identified, these issues are overcome by connecting with people at the nearby University of Oxford, and with my wider professional network.

For me the chance to work abroad is a big draw for a scientific career; it built my confidence and expanded my professional network as well as providing a great experience. Coming back to the UK was right for me at the time but I’d not rule out going abroad again.


© The Physiological Society

‘Establishing a life outside of work has been vital in putting my work here into perspective, and makes those inevitable scientific frustrations far easier to deal with.’ – Chris Shannon, University of Texas Health Science Centre, USA

The quest for the Holy Grail of lectureship
by Gisela Helfer, Lecturer, University of Bradford, UK

After I graduated in Zoology at the University of Salzburg, Austria, I worked at the Max Planck Institute for Ornithology in Andechs, Germany. Here I found my love for science in general and chronobiology in particular. From Andechs, I started my northwards journey, first to do a PhD at the University of Birmingham and then to postdoc at the Rowett Institute in Aberdeen. Throughout my journey, I was very fortunate to meet some amazing scientists, mentors as well as peers, and it was always my ambition to succeed in academia. Six years of postdocing, three moves and two children later, I finally found the Holy Grail in beautiful Yorkshire. In March 2016, I started my permanent lectureship at the University of Bradford.

Academia has one of the longest apprenticeships that I am aware of. Undergraduate studies, plus/minus masters studies, PhD studies and then several years of postdocing. For me, this totalled to 14 years of apprenticeship. Despite this long training, I was little prepared for the job of a lecturer. Yes, I had some teaching experience. I supervised students in the lab, I occasionally lectured to undergrads and I even worked a few months as a teaching fellow. In my CV I called this ‘extensive teaching experience’ – little did I know. Because in reality I spent all my days and often nights (the joys of circadian rhythms research) in the lab or in the animal house. And I loved every minute of it!


© Wellcome Library, London.

Now, I am rarely in the #Helferlab. The brand-new set of pipettes that I proudly bought from my first grant is now exclusively used by my students, while I spend my time rushing from place to place. I run to see undergrads or I run to one of my countless meetings.

I admit that I miss being a postdoc. I miss being in the lab from morning to evening, I miss having a supervisor who keeps me right (although my mentor at the Rowett is only a phone call away) and I miss the untroubled life of only being responsible for the next set of experiments. Of course, I do not miss the dreadful months before the contract comes to an end.

Despite all of this, I enjoy being a lecturer. While the holy grail is not as shiny and golden as I thought it would be, the journey was certainly worth it, and I would do it all over again. Next goal: professorship.

This article was compiled by Jo Edward Lewis. You can read more testimonies in the original article in our magazine, Physiology News.

Diet, exercise or drugs – how do we cure obesity?

by Simon Cork, Imperial College London, @simon_c_c

October 11th is officially “World Obesity Day”, a day observed internationally to promote practical solutions to end the obesity crisis. The term “obesity crisis” or “obesity epidemic” is often repeated by the media, but how big is the problem? Today, over 1.9 billion adults worldwide are overweight or obese. By 2025, this is projected to increase to 2.7 billion with an estimated annual cost of 1.2 trillion USD. Of particular concern is that 124 million children and adolescents worldwide are overweight or obese. In the UK, this equates to 1 in 10 children and adolescents and is projected to increase to 3.8 million by 2025. We know that obesity significantly raises the risk of developing 11 different types of cancer, stroke, type 2 diabetes, heart disease and non-alcoholic fatty liver disease, but worryingly, we now know that once someone becomes obese, physiological changes to the body’s metabolism make long-term weight loss challenging.

Our understanding of the physiology of food intake and metabolism and the pathophysiology of obesity has grown considerably over the past few decades. Obesity was seen, and often still is seen, as a social problem, rather than a medical issue: a lack of self-control and willpower. We now know that physiological changes occur in how our bodies respond to food intake. For example, hormones which are released from the gut following food intake and signal to the brain via the vagus nerve normally reduce food intake. However, in obesity, the secretion of these hormones is reduced, as is the sensitivity of the vagus nerve. The consequence of this is a reduced sensation of feeling full.


Imaging of the hypothalamus (a key region for keeping food intake at a balanced level) shows a reduction in activity following food intake in lean men, an effect which was absent in obesity. This effect may relate to a reduction in the body’s responses observed following food intake in obesity, such as balancing blood sugar and signalling that you are full. Furthermore, numerous studies have shown that obese individuals have a reduced availability of dopamine receptors, the structures on cells that respond to the pleasure chemical dopamine, in key brain regions associated with reward. Whether the reduction in dopamine receptor availability is a cause or consequence of obesity remains to be fully explored, but it is likely to be a combination of both of these factors. Individuals with a gene called the Taq1 A1, associated with a decreased availability of dopamine receptors, are more likely to become obese, suggesting that decreased responsiveness to high calorie foods leads to increased consumption in order to achieve the same level of reward. (Interestingly, this same gene is also associated with an increased risk of drug addiction). However, much like drug addiction, hyper-stimulation of the dopamine system (i.e. by consuming large quantities of dopamine-secreting, high calorie foods) can in turn lead to a reduction in dopamine receptor levels, thus creating a situation where more high calorie foods are required to stimulate the same level of reward.

It is therefore clear that obesity is not simply a manifestation of choice, but underpinned by complex changes in physiology which promote a surplus of food consumption, called positive energy balance. From an evolutionary standpoint, this makes sense, as maintaining a positive energy balance in times of abundant food would protect an individual in times of famine. However, evolution has failed to keep up with modern society, where 24-hour access to high calorie foods removes the threat of starvation. The good news is that we know that weight loss as small as 5% can yield significant improvements in health, and can often be managed without significant modification to lifestyle.



Presently, treatment options for obesity are limited. The first line treatment is still diet and exercise; but as the above examples of how our physiology changes show, maintaining long term weight loss through self-control alone is almost always impossible. However, the future does look bright, with new classes of drugs either recently licenced, or in production. Saxenda (a once-daily injectable drug which mimics the gut hormone GLP-1 made by Novo Nordisk) has recently been licenced for weight loss in patients with a BMI greater than 30. However, after 56 weeks treatment, average weight loss was a modest 8kg. Likewise Orlistat (which inhibits absorption of dietary fat, made by Roche) has been on the market for a number of years and shows average weight loss of around 10%. However, it is associated with unpleasant side effects, such as flatulence and oily stools. Presently, bariatric surgery is the only treatment that shows significant, long term weight loss (around 30%, depending on the surgical method used) and is also associated with long-term increases in gut hormone secretion and vagus nerve sensitivity.  Research is currently underway to assess whether the profile of gut hormones observed post-surgery can be mimicked pharmacologically. Studies have shown that administering select gut hormones in combination results in a reduction in body weight and food intake greater than the sum of either hormone when administered in isolation. This observed synergy between gut hormones will undoubtedly form the basis for future pharmacotherapies with improved efficacy, with various combinations currently in both clinical and pre-clinical trials.

For healthcare policy makers, the future obesity landscape does not make for happy reading. A combination of better therapies and improved public health messages are undoubtedly needed to stem the rising tide. However, both policy makers and society as a whole should be mindful that changes in ones physiology mean maintaining long-term weight loss through diet and exercise alone are unlikely to be the whole answer.