Pediatric Endocrine-Neuroendocrine-Sports Endocrine Research

-Areas of Focus

The Female Athlete Triad

The female athlete triad is the interrelationship of low energy availability, menstrual dysfunction and decreased bone mineral density. Upto 62% of women participating in sports involving running activities and other endurance sports experience menstrual dysfunction, as compared to only 2-5% of the general population. A major concern associated with the female athlete triad is low bone mineral density. Decreased bone mineral density is reported in 22-50% of female athletes as compared to 12% of the normal population. Decreased bone mineral density during adolescence puts these athletes at a higher risk for fracture both immediately and in later life. Therefore, it is imperative to address this serious and widespread issue. Furthermore, estrogen deficiency in those with menstrual dysfunction may have an impact on cognitive and neuropsychiatric outcomes.

We have demonstrated through an R01 grant that low fat mass and changes in adipokines (such as leptin) and hormones regulated by fat (such as ghrelin and cortisol) predict changes in LH pulsatility patterns that lead to amenorrhea in adolescent and young adult athletes 14-25 years old. We have also shown that amenorrhea in athletes is associated with marked changes in bone density, structure and strength, and that the beneficial effects of mechanical loading on bone are lost in athletes who are hypogonadal. Finally, we have demonstrated that physiologic estradiol replacement (with cyclic progesterone) improves bone density and structure, verbal memory, executive function, and eating behavior in oligo-amenorrheic athletes.

Publications

Current research studies aim at further investigating:

• The effect of transdermal estradiol replacement (with cyclic progesterone) on cognitive flexibility, reward responsiveness and eating behavior Learn more.

Anorexia Nervosa

We have shown that girls with anorexia nervosa (AN) have alterations in multiple neuroendocrine axes including the hypothalamic-pituitary adrenal axis, the growth hormone- insulin like growth factor-1 (IGF-I) axis, the hypothalamic-pituitary- thyroid axis and multiple appetite regulating peptides. These hormonal alterations in turn contribute to a state of hypothalamic amenorrhea. Hypogonadism has deleterious effects on bone and certain psychiatric endpoints.

We have demonstrated that low bone density is prevalent in adolescent girls and boys with anorexia nervosa and is associated with decreased bone turnover. Hormonal alterations that predict low bone density in this disorder include hypogonadism, a nutritionally acquired resistance to growth hormone effects, low IGF-I levels, and high cortisol levels. Weight gain and resumption of menses are associated with some improvement in bone parameters, however, residual deficits persist, raising concerns regarding inadequate catch-up and suboptimal peak bone mass acquisition. Our studies have shown that although oral estrogen-progesterone combination pills are not effective in increasing bone density in adolescents with AN, likely because of the IGF-I suppressive effects of oral estrogen, transdermal estrogen replacement (with cyclic progesterone) is effective in increasing bone accrual rates in AN girls to approximate accrual rates in controls. However, complete catch-up does not occur, likely because of residual deficits in other hormones, such as IGF-I. We have also shown that giving IGF-I for a short duration increases markers of bone formation.

In addition, women with anorexia nervosa with higher cortisol levels have lower bone density and higher measures of anxiety and depression. Our studies have also demonstrated a beneficial effect of physiological estrogen replacement (as the transdermal estradiol patch with cyclic progesterone) on measures of anxiety in this population, with a reduction in trait anxiety over an 18-month period. Finally, we have shown that estrogen replacement prevents the increase in body dissatisfaction, interoceptive awareness and asceticism observed in girls with anorexia nervosa who gain weight. Publications

Our current research aims at investigating:

• The efficacy of IGF-I replacement in increasing bone density in teenagers with anorexia nervosa receiving transdermal estrogen replacement (with cyclic progesterone), while also providing supplements that have a beneficial impact on bone Learn more.
• Homeostatic and hedonic food motivation pathways using functional MRI in relation to appetite regulating hormones and eating behaviors in order to determine predictors of long-term trajectories of these disorders Learn more.
• The effect of transdermal estradiol replacement (with cyclic progesterone) on cognitive flexibility, reward responsiveness and eating behavior Learn more.

Low-Weight Eating Disorders

Brain Study: Eating disorders are heterogeneous illnesses characterized by aberrant behaviors of extreme dietary restriction, binge eating, and purging. The course often involves adolescent onset, and in more than half of individuals, transition from predominantly restrictive to binge/purge behaviors. The pathophysiology of low-weight eating disorders and mechanisms that underlie restricting vs. binge/purge phenotypes are almost entirely unknown. A critical knowledge gap is the neurobiology underlying the developmental trajectory of these illnesses (e.g. transition from primary restriction to binge eating or purging or recovery).

Our current research aims at investigating:

• Homeostatic and hedonic food motivation pathways using functional MRI in relation to appetite regulating hormones and eating behaviors in girls 10-21 years old with low-weight eating disorder behaviors in order to determine predictors of long-term trajectories of these disorders Learn more.

Obesity

Although adolescents with obesity are known to suffer from significant cardiometabolic risk, determinants of such risk were not clear when we started working in this field. We showed that adolescent girls with obesity have lower growth hormone (GH) and higher cortisol than normal-weight controls, and these hormonal changes are predictive of greater visceral compared with subcutaneous fat. Visceral fat, in turn, is a strong determinant of markers of cardiovascular risk and also of lower bone density, likely through the secretion of specific adipokines and inflammatory cytokines. We know that adults with obesity who undergo weight-loss surgery are at risk for bone loss and decreased bone strength. However, we do not know the effects of such surgery on bone accrual and outcomes in teenagers and young adults.

Publications

Our current research aims at investigating:

• The impact of Roux-en-Y gastric bypass or sleeve gastrectomy vs. no surgery on bone density, structure and strength outcomes in adolescents and young adults 14-25 years old with moderate to severe obesity using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT). We are also studying the impact of surgery on the amount of fat in the body and within bones, as well as hormonal changes that may be responsible for bone loss following surgery. Learn more.
• The impact of Roux-en-Y gastric bypass or sleeve gastrectomy vs. no surgery in youth on insulin secretion and sensitivity

Diabetes and Bone Health

We are interested in the effect of type 1 diabetes on bone density. We have now completed our recruitment of girls with type 1 diabetes and are now looking for boys with type 1 diabetes who are otherwise healthy in order to learn how their bone density changes over time. Our current research aims at investigating:

• Bone accrual in adolescent girls with type 1 diabetes 10-16 years old vs. controls using dual energy x-ray absorptiometry (DXA) and high resolution peripheral quantitative computed tomography (HR-pQCT) (ongoing study; recruitment complete) Learn more.
• Cross-sectional differences in bone density and structure (using DXA and HR-pQCT) and their determinants in boys with type 1 diabetes vs. controls ages 6-20 years
• Bone accrual in boys with type 1 diabetes 6-20 years old vs. controls using DXA and HR-pQCT

Autism Spectrum Disorders

Following anecdotal reports of fracture in children with autism spectrum disorders (ASD), we worked on studies examining bone mineral density (BMD) in peripubertal boys with ASD, and fracture prevalence in children and adults with ASD. We found a higher prevalence of low bone density in boys with ASD compared with typically developing controls predicted by lower dietary vitamin D intake and lower levels of physical activity. Boys with ASD also have higher levels of morning cortisol and hypotonia than typically developing controls. Bone microarchitectural parameters are also impaired in ASD, with reductions in bone strength estimates (stiffness and failure load) at the ultradistal radius and distal tibia. Further, although pubertal bone accrual is similar to that in controls, BMD in children with ASD remains low over a 4-year follow-up period, suggesting that low BMD is a consequence of prepubertal factors, such as low physical activity. Finally, there is a higher prevalence of hip and spine fracture in children and adults with ASD compared with controls. We are currently working on a study assessing effects of oxytocin administration on bone outcomes in children with ASD.

Publications

For more information, please visit the Pediatric Neuroendocrine Research website

Frequently Asked Questions

Will scheduling be a problem since I’m a full-time student?

We understand that most participants are in high school or college and have very busy schedules. We respect your time commitments and work hard to plan visits around your schedules so that participants do not have to miss their classes, jobs, or team commitments. For example, some visits can take place on weekends.

I will be out of town for the summer months. Will that be an issue for scheduling my visits?

Not at all! We can coordinate visits when you are here, or schedule these at facilities closer to you. If you let us know ahead of time when you’ll be away, we can work out the dates so they fit best with your schedule.

Is it safe for me to participate?

All the components of this study have been approved by a human safety board called the Institutional Review Board to ensure that the protocol and all the procedures we do are safe for participants. Additionally, if the study you are involved in includes medications, these medications are natural hormones given in replacement doses.

What is the purpose of the CT scan for bone studies?

The CT scan is an imaging study that helps us visualize the structure of bones at a microscopic level. This gives us a more detailed picture of bone than a DXA scan does, and may better predict fracture risk. The CT scan will help us determine how bone structure is affected by hormonal changes or your specific condition.

How does the fMRI scan work?

The term fMRI stands for functional MRI. This means that the MRI scan is done when the subject is actually doing some tasks (and hence the term functional). This scan helps us visualize the brain when subjects perform some tasks in the scanner.

The scans take place at the Martinos Center in Charlestown or at McLean Hospital. You can either meet the study coordinator at the respective site, or take a shuttle from the MGH main campus with the coordinator.

Once there you will be asked to change into scrubs and remove all metal before entering the scanner. The study staff will help you into the machine where you will be lying down and looking at a screen. The scan will take about an hour and during the scans you will be responding to behavioral tasks presented on the screen.

Current Studies

Studies currently recruiting:

• The Role of Estrogen in the Neurobiology of Eating Disorders
• Bone Metabolism in Adolescents Undergoing Bariatric Surgery
• Determinants of bone microarchitectural compromise in youth with type 1 diabetes

Publications