Jennifer L. Carlson

The Pathophysiology of Amenorrhea in the Adolescent

Menstrual irregularity is a common occurrence during adolescence, especially within the first 2–3 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical morbidity, which differs depending on whether the adolescent is estrogen‐deficient or estrogen‐replete. Estrogen‐deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen‐replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise‐induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities.

Obstacles in the Optimization of Bone Health Outcomes in the Female Athlete Triad

Maintaining low body weight for the sake of performance and aesthetic purposes is a common feature among young girls and women who exercise on a regular basis, including elite, college and high-school athletes, members of fitness centres, and recreational exercisers. High energy expenditure without adequate compensation in energy intake leads to an energy deficiency, which may ultimately affect reproductive function and bone health. The combination of low energy availability, menstrual disturbances and low bone mineral density is referred to as the ‘female athlete triad’. Not all athletes seek medical assistance in response to the absence of menstruation for 3 or more months as some believe that long-term amenorrhoea is not harmful. Indeed, many women may not seek medical attention until they sustain a stress fracture.This review investigates current issues, controversies and strategies in the clinical management of bone health concerns related to the female athlete triad. Current recommendations focus on either increasing energy intake or decreasing energy expenditure, as this approach remains the most efficient strategy to prevent further bone health complications. However, convincing the athlete to increase energy availability can be extremely challenging.Oral contraceptive therapy seems to be a common strategy chosen by many physicians to address bone health issues in young women with amenorrhoea, although there is little evidence that this strategy improves bone mineral density in this population. Assessment of bone health itself is difficult due to the limitations of dual-energy X-ray absorptiometry (DXA) to estimate bone strength. Understanding how bone strength is affected by low energy availability, weight gain and resumption of menses requires further investigations using 3-dimensional bone imaging techniques in order to improve the clinical management of the female athlete triad.

Association of the Female Athlete Triad Risk Assessment Stratification to the Development of Bone Stress Injuries in Collegiate Athletes

Background: The female athlete triad (referred to as the triad) contributes to adverse health outcomes, including bone stress injuries (BSIs), in female athletes. Guidelines were published in 2014 for clinical management of athletes affected by the triad. Purpose: This study aimed to (1) classify athletes from a collegiate population of 16 sports into low-, moderate-, and high-risk categories using the Female Athlete Triad Cumulative Risk Assessment score and (2) evaluate the predictive value of the risk categories for subsequent BSIs. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 323 athletes completed both electronic preparticipation physical examination and dual-energy x-ray absorptiometry scans. Of these, 239 athletes with known oligomenorrhea/amenorrhea status were assigned to a low-, moderate-, or high-risk category. Chart review was used to identify athletes who sustained a subsequent BSI during collegiate sports participation; the injury required a physician diagnosis and imaging confirmation. Results: Of 239 athletes, 61 (25.5%) were classified into moderate-risk and 9 (3.8%) into high-risk categories. Sports with the highest proportion of athletes assigned to the moderate- and high-risk categories included gymnastics (56.3%), lacrosse (50%), cross-country (48.9%), swimming/diving (42.9%), sailing (33%), and volleyball (33%). Twenty-five athletes (10.5%) assigned to risk categories sustained ≥1 BSI. Cross-country runners contributed the majority of BSIs (16; 64%). After adjusting for age and participation in cross-country, we found that moderate-risk athletes were twice as likely as low-risk athletes to sustain a BSI (risk ratio [RR], 2.6; 95% confidence interval [95% CI], 1.3-5.5) and high-risk athletes were nearly 4 times as likely (RR, 3.8; 95% CI, 1.8-8.0). When examining the 6 individual components of the triad risk assessment score, both the oligomenorrhea/amenorrhea score (P = .0069) and the prior stress fracture/reaction score (P = .0315) were identified as independent predictors for subsequent BSIs (after adjusting for cross-country participation and age). Conclusion: Using published guidelines, 29% of female collegiate athletes in this study were classified into moderate- or high-risk categories using the Female Athlete Triad Cumulative Risk Assessment Score. Moderate- and high-risk athletes were more likely to subsequently sustain a BSI; most BSIs were sustained by cross-country runners.

Assessment of sex differences in bone deficits among adolescents with anorexia nervosa.

OBJECTIVE The objective of this study was to compare sex differences in bone deficits among adolescents with anorexia nervosa (AN) and to identify other correlates of bone health. METHOD Electronic medical records of all patients 9-20 years of age with a DSM-5 diagnosis of AN who were evaluated by the eating disorders program at Stanford with dual-energy X-ray absorptiometry (DXA) between March 1997 and February 2011 were retrospectively reviewed. Whole body bone mineral content Z-scores and bone mineral density (BMD) Z-scores at multiple sites were recorded using the Bone Mineral Density in Childhood Study (BMDCS) reference data. RESULTS A total of 25 males and 253 females with AN were included, with median age 15 years (interquartile range [IQR] 14-17) and median duration of illness 9 months (IQR 5-13). Using linear regression analyses, no significant sex differences in bone deficits were found at the lumbar spine, total hip, femoral neck, or whole body when controlling for age, %mBMI, and duration of illness. Lower %mBMI was significantly associated with bone deficits at all sites in adjusted models. DISCUSSION This is the first study to evaluate sex differences in bone health among adolescents with AN, using novel DSM-5 criteria for AN and robust BMDCS reference data. We find no significant sex differences in bone deficits among adolescents with AN except for a higher proportion of females with femoral neck BMD Z-scores <-1. Degree of malnutrition was correlated with bone deficits at all sites.

The Menstrual Cycle

Menstrual disorders are common findings among female athletes. Female athletes have been shown to have higher rates of a range of disorders from luteal phase defects to primary and secondary amenorrhea. Additionally, female athletes have later menarche when compared to non-athletes. Aesthetic, endurance, and weight class-based sports, in addition to higher training volumes and lower body weights, seem to place athletes at greater risk for menstrual disorders. Hypothalamic-pituitary-ovarian (HPO) axis suppression, often referred to as hypothalamic amenorrhea, is thought to be the most frequent etiology of the underlying dysfunction in athletes. HPO suppression appears to be secondary to a negative energy balance resulting from insufficient caloric intake for the degree of energy expenditure. More recently, the hormone leptin has been identified as a possible link between energy status and hormonal functioning, although multiple other factors may also be involved. In the evaluation of menstrual disorders, a thorough history and physical examination is warranted. Serum and radiologic tests are often indicated to fully evaluate any underlying pathology. If hypothalamic amenorrhea is determined to be the issue, then restoring an appropriate energy balance is critical for restoring menstrual function.