 Up next, Dr. Catherine Ackerman, my apologies. Medical School at John Hopkins University School of Medicine. Dr. Ackerman is a sports medicine physician and the medical director of the Female Athlete Program in the Division of Sports Medicine at Boston Children's Hospital. Her interests include female athletes, rowing injuries, and endocrinology, as well as the female athlete triad. He was presented locally and internationally about the female athlete triad as well as diabetes and exercise. Dr. Ackerman is a former national team lightweight rower and a team physician for USA rowing. Welcome, Dr. Ackerman. I'm Kate Ackerman, thank you for having me. I'm going to be talking about relative energy deficiency in sport. I have no disclosures other than I'm a member of the International Olympic Committee's Relative Energy Deficiency in Sport and Female Athlete Working Group. So around 2012, the IOC decided that they should do an update in their female athlete triad position statement. Female athlete triad, the terminology had been around since the early 1990s, and we know now that this is the interrelationship between low energy availability, menstrual dysfunction, and bone health. And so when the IOC Working Group met, they were acknowledging that relationship amongst those three entities, but also wanted to expand upon them and talk about the other health and performance consequences of low energy availability and also bring some attention to the fact that men can also have low energy availability. So they came up with this term Relative Energy Deficiency in Sport, or REDS, and they had a position statement that was published in 2014. It has since been updated for a 2018 edition. So they have these two spoken wheel diagrams. These are based off of Nama Konstantini's work. She was a member of the group. And basically the idea is that there are various health consequences, as you can see in this picture. And so the triad is still there. Relative Energy Deficiency is still leading to impaired menstrual function and impaired bone health, but then there are the other aspects. So endocrine function, metabolic function, hematologic function, growth and development, psychological aspects, cardiovascular consequences, GI issues, and immunologic effects. They have this potential performance effects wheel, and this is really talking about increased injury risk, decreased training response, impaired judgment, decreased coordination, decreased concentration, irritability, depression, decreased glycogen stores, decreased muscle strength, and decreased endurance performance. So we start with the triad. We know that this is well established. There are endocrine effects as well. But when we look at different things that happen with low energy availability in female athletes, we know that there's a decrease in BMI, fat mass and lean mass, a decrease in FSH, LH, estradiol, and androgens, a decrease in insulin, glucose, IGF-1, T3, and leptin, and an increase in fasting PYY, ghrelin, cortisol, and growth hormone resistance. Now everything on this slide has an effect on bone, but the things in green have a very positive effect on bone, and the things in red have a very negative effect on bone. And unfortunately, in situations with low energy availability, things are going in the wrong direction. So all of these things have a negative effect on bone when they're impaired during relative energy deficiency. When we look at the thyroid specifically in a cross-sectional study, there was lower T4 and T3 in amenorrheic athletes versus eumenorrheic athletes in healthy controls. Women who were randomized to groups of four days of normal or low energy availability with different exercise prescriptions found that low energy availability led to decreased T3 and free T3, and an increase in T4 and reverse T3. And T3 really seems to be the marker here. Exercise quantity and intensity did not affect thyroid hormone levels. In another study looking at amenorrheic athletes, eumenorrheic athletes in healthy controls, again, focusing on T3, there was lower T3 and free T3 in the amenorrheic versus the healthy controls, and then lower free T3 in the amenorrheic athletes versus eumenorrheic athletes. Finally, in another study of just eumenorrheic non-athletes, they had four days of exercise with different energy availabilities. And there was a drop in T3 and free T3 between 19 and 25 kilocals per Kg of fat-free mass per day. And when these people were even more energy restricted, down to 10.8 to 19 kilocals per Kg of fat-free mass per day, there was actually an increase in T4 and reverse T3 in addition to the drop in T3 and free T3. So the take-home point is T3 may be a very helpful marker in terms of energy availability. When we talk about the metabolic effects, when we look at metabolic rate, there was a small study of normal weight women with different exercise and caloric intake alterations for three months. There was severely energy restricted, so they had a caloric deficit of about 1,000 calories per day. There was moderately restricted with a deficit of about 633 calories per day or those with balanced energy. Weight loss occurred in the severely energy restricted and the moderately energy restricted, but significantly less than was predicted. RMR decreased by about 6% in the moderately restricted. And in the severely restricted, RMR did not change for the entire group, but those whose RMR decreased lost more weight and had a higher baseline RMR than those whose RMR did not decrease. The energy deficit and adaptive changes in RMR explained 54% of the weight loss. So clearly resting metabolic rate was affected by that energy restriction. When we talk about the hematologic effects, many athletes with reduced energy availability have iron deficiency. Iron deficiency may worsen the hypometabolic state associated with decreased energy availability. So T4 synthesis and T4 to T3 conversion rely on iron. Iron deficiency may promote energy deficiencies, so it shifts ATP production from oxidative phosphorylation to anaerobic pathways. And iron is needed for reproductive function, so for follicular development and corpus luteum function. Additionally, bone health may be further impaired by iron deficiency. And some have suggested even putting iron deficiency in the center of that triad diagram. So it clearly has a role that's very intertwined with relative energy deficiency. When we talk about growth and development, we've probably all seen athletes who have fallen off their growth curve. Either they've had a significant drop in their weight or they've stopped growing in terms of their stature. And when their nutritional intake was improved, they actually had a resumption of their growth at both with their weight and their stature. In terms of psychological effects, there can be many. As one example, drive for thinness we can use. So this was assessed in exercising and sedentary women using the eating disorder inventory. Athletes with a high drive for thinness versus athletes and non-athletes with a normal drive for thinness scored higher on questions about bulimia and effectiveness and cognitive restraint. They experienced more amenorrhea and oligomenorrhea versus the other two groups. They had lower resting energy expenditure per fat free mass and resting energy expenditure for predicted resting energy expenditure. More were classified as energy deficient. They had lower total T3 and higher ghrelin. When we talk about the cardiovascular effects, we know that premenopausal women with anorexia nervosa have elevated lipid levels. Theories for this include interactions of estrogen deficiency, liver dysfunction, dehydration, reduced cholesterol turnover, decreased T3 again and delayed cholesterol metabolism. Coronary artery disease is one of the top causes of death in premenopausal women in the US, Canada, UK and Australia. And retrospective data suggests development of early coronary artery disease in some older premenopausal women with a history of functional hypothalamic amenorrhea, which is very often tied to low energy availability. We know that estrogen stimulates the vascular endothelium. This leads to increased endothelial drive nitric oxide and nitric oxide leads to vasodilation, which our muscles need for good optimal performance. Nitric oxide also has anti-athlor squarata properties. Estrogen and regular aerobic physical activity are independently associated with enhanced synthesis and or bioavailability of endothelial nitric oxide. So flow mediated dilation or FMD can actually assess endothelial function in the brachial artery, so along the arm. And there's a 95% positive predictive value of abnormal brachial dilation in predicting coronary endothelial dysfunction. So we can use this peripheral brachial artery as a surrogate for what's happening in the heart. So FMD is actually lower in amenorrhea cathletes than oligomenorrhea cathletes and eumenorrhea cathletes. And serum estrogen levels positively correlated with vascular function. In amenorrhea cathletes who regained their menstrual cycles, the increased estrogen levels were associated with restored vascular function. Moving on to the GI system. There's not a lot of athletes specifically about this, but in a systematic review of 123 articles of anorexia nervosa patients, there was delayed gastric emptying, increased intestinal transit time and constipation. These amorexia patients also had elevated liver enzymes. So we did a study of 1,000 female sports medicine clinic patients. They were between the ages of 15 and 30, and they had to exercise at least four hours per week. We decided to use surrogate markers for low energy availability. There was self-report of disordered eating or eating disorder. There was the beta Q, which is the brief eating disorder questionnaire for athletes, or there was the eating disorder screen for primary care. We had about an 85% response rate, and we found actually that there was low energy availability or a positive answer to those three different screens in 47.3% of our clinic patients. So these were all comers coming into sports clinic for various injuries, sports injuries. There was the 1.5 times greater odds of GI complaints in the low energy availability group versus the adequate energy availability group. In terms of the immunologic system, we know that athletes with high training loads often experience impaired immune function and frequent upper respiratory infections. There was a study of elite Australian athletes prepping for Rio 2016, and low energy availability was measured by the leaf Q. This is the low energy availability questionnaire for female athletes. And those who had low energy availability had an increased odds of illnesses. So for example, upper respiratory and GI tracts had increased odds of body aches and head-related symptoms in the prior month. So let's move on quickly to the potential performance effects of regs. And going around this circle, here's another area that needs more research. But one great study is a study looking at junior elite female swimmers. So these are women who were 15 to 17 years old. There were cyclic women, or women who got their menstrual cycle every month, and ovarian suppressed women based on the estradiol and progesterone levels. These levels were monitored every two weeks, over 12 weeks. The ovarian suppressed had suppressed estrogen and progesterone as you would expect throughout the season. And they had a decrease in T3 and IGF-1 at week 12 versus the cyclic or the ones who were menstruating. Energy intake and energy availability was lower in the ovarian suppressed athletes. And really, really important here is the ovarian suppressed athletes had a 9.8% increase in their 400 meter swim time. So they actually got slower while the cyclic athletes had an 8.2% decrease so they got faster. So over the course of three months of training, those who were not getting their menstrual cycle actually got slower while the others got faster. And I love describing this study to a lot of my athletes to kind of convince them when they need to gain weight and improve their energy intake. In our survey, we found a 1.47 times greater odds of decreased endurance performance with low energy availability versus the adequate energy availability group. In another study we did, we looked at 175 female athletes ages 14 to 25 years and we did DEXAs on them and we used HRPQCT or high resolution peripheral quantitative CT to look at their bone microarchitecture. We asked them about their history of fracture and you can see in this picture below, we have amenorrheic athletes, eumenorrheic athletes in white and the non-athletes in gray. The amenorrheic athletes, this is the percentage of subjects with stress fractures. So over the course of their lifetime, the amenorrheic athletes had more and more stress fractures. The eumenorrheic athletes had some stress fractures around the ages of 13, 15, 16. And this is a time when people's peak height velocity is a bit faster than their bone mineralization so they're more susceptible to fracture. And then there are no athletes, no non-athletes on this diagram because they don't have any stress fractures if they're not doing something repetitively. But you can see that the amenorrheic athletes just went up and up and up in terms of their percentage of stress injuries. We also found that in amenorrheic athletes who had had two or more stress injuries, they had worse bone density and they had worse bone microarchitecture than those who had not had these stress injuries. In terms of decreased training response, we have that prior study in swimmers. In our survey, we asked, compared to your peers, does it take a longer time for you to recover from training for your sport? And the low energy availability group did answer at a higher percentage that yes, this was true. Looking at all the other performance effects, most of these were supported. So we did not look at the decreased glycogen stores. That would be hard with the survey. We didn't look at decreased muscle strength. And but everything else showed a higher rate in those who were relative energy deficient. The only thing we didn't see was increased injury risk. But this was a sports clinic where people were coming in with injury. In terms of decreased muscle strength, neuromuscular performance assessed by in-elite amenorrheic athletes and new menorrheic athletes. Knee muscular strength and knee muscular endurance was worse in amenorrheic athletes. And reaction time was 7% longer versus you menorrheic athletes. There was a decrease in leg fat free mass, glucose, estrogen, T3 and an increase in cortisol levels that correlated with the fine. So overall with REDS, the medical profession can often spot it, but we need to prove it to the athlete. We have to look for different signs and symptoms. You can see amenorrhea or low FSH-LH and estradiol, decreased libido, low testosterone, low white blood cell count, low iron or ferritin, low T3, low vitamin D, increased LFTs, altered lipids, decreased performance, decreased bone mineral density, low BMI and low fat mass. Future directions include studies exploring other health and performance effects of low energy availability in female athletes, male athletes, para athletes, studies determining efficacy or return play protocols, definitive hormonal and other therapy studies for REDS, more awareness and prevention. And so I just want to overall thank everybody, thank our funding, thank Boston Children's, MGHR International Olympic Committee and our patients and thank you to the USOPC for this conference.