Prevention for secondary amenorrhea during teenage and low BMI in their 20s might lead to an appropriate BMD.
Low energy availability with or without disordered eating, menstrual dysfunction, and low bone mineral density (BMD), collectively known as female athlete triad (FAT), are often observed among female athletes.1 In addition, the International Olympic Committee has proposed the term relative energy deficiency in sports, which includes FAT.2,3 Female athletes with amenorrhea have a high risk for low BMD or osteoporosis.1–12 Moreover, previous studies showed that female athletes with a Z-score ≤−1 and those with a Z-score of ≤−2 in the dual-energy x-ray absorptiometry (DXA) of the lumbar spine have 3.6 and 4.5 times higher risk of stress bone injuries, respectively, compared with athletes with normal BMD.7 Hence, BMD protection could lead to a decreased risk of injuries, for example, stress fractures, and decreased chances of a lifetime of bone weakness.
Some of the factors influencing BMD include genetics, nutrition, hormones, and exercise.8,13 Especially in women, estradiol plays essential roles in bone metabolism.14-16 Peak bone mass (PBM) is considered to occur around the age of 20 years,13,17 and menstrual state during teenage years plays a vital role for an appropriate BMD.6 Female athletes who have late menarche or primary amenorrhea exhibit a 4-fold higher risk of low BMD compared with those without menstrual abnormalities.6 Comparing the BMD of femoral neck bone sites, amenorrheic athletes had lower levels (8%) than eumenorrheic athletes.18 Amenorrheic gymnasts had lower BMD at lumber spine than athletes without amenorrhea.19 As a cumulative number of FAT risk factors increases, low BMD risk increases.4 In addition, late menarche and low BMI were risk factors for low BMD.4 However, no reports investigating the relationship between secondary amenorrhea during teenage years and BMD in female athletes in their 20s exist. Both the American College of Sports Medicine (ACSM) and International Olympic Committee (IOC) recommend FAT annual screening with Triad Consensus Panel Screening Questions as a part of the preparticipation physical evaluation in female athletes.1 The treatment for FAT is improvement of low energy availability and energy status, which should be normalized through modification of energy intake and exercise expenditure.1 Regarding low BMD, although it has been reported that gaining weight and resuming menstruation leads to improving BMD levels, some athletes do not show improvement.6 Thus, as treatment for low BMD in young athletes has not been established, we need to clarify correlation factors for low BMD, and early detection of low BMD is crucial for female athletes.
In this study, we investigated the BMD in female athletes older than 20 years, which is when PBM is achieved, and clarified whether secondary amenorrhea in their teens influenced the BMD in their 20s. We hypothesized that the occurrence of secondary amenorrhea in teenage athletes might be a determining factor for future BMD formation.
Elite female athletes, or those participating in high-level competition, older than 20 years who visited the medical center of Japan Institute of Sports Sciences (JISS) from 2013 to 2015 were included in the study. We excluded female athletes who had been taking hormone therapies or using oral contraceptives or transdermal estradiol and amenorrheic athletes who were first diagnosed with polycystic ovarian syndrome during the medical examination. A total of 210 subjects were included in the final analysis.
The sports of the participants include middle-/long-distance running (48), soccer (46), track events other than middle-/long-distance running (18), rhythmic gymnastics (14), swimming (12), sailing (12), rugby (11), fencing (6), skiing (5), speed skating (4), tennis (4), gymnastics (4), cycling (4), volleyball (3), rifle shooting (3), basketball (2), archery (2), badminton (2), boating, triathlon, American football, cheer dance, handball, hockey, ice hockey, wrestling, snowboarding, and boxing (1 each) (Table 1).
Information on the following was obtained: age, age of menarche, last menstrual period, menstrual cycle, duration of amenorrhea at present, whether the participants had greater than 1 year of menstrual deficiency in their teens, age they started with their current event/sport, training frequency (days per week), history of stress fracture, and time of last training before examination.
The age of menarche and menstrual cycle was evaluated by a gynecologist. Athletes with a regular menstrual cycle, from 25 to 38 days, were identified as “eumenorrheic athletes (EA)” and those with amenorrhea greater than 3 months as “amenorrhea athletes (AA).” One hundred fifty-two of the 210 athletes were EA, and the remaining 58 athletes were AA. Furthermore, the subjects with secondary amenorrhea for greater than 1 year were identified as “secondary amenorrhea in their teens.”
Grouping of Athletes With or Without Amenorrhea in Their Teens
We investigated the BMD in relation to the athletes' menstrual condition in their teens and 20s. Twenty-nine athletes had secondary amenorrhea in their teens, greater than 1 year of menstrual deficiency, and amenorrhea in their 20s (group A); 29 athletes had regular menstruation in their teens and secondary amenorrhea in their 20s (group B); and 152 athletes had regular menstruation in their teens and 20s (group C). None of the athletes had secondary amenorrhea in their teens and regular menstruation in their 20s.
Blood Collection and Assay
Blood samples were obtained from the antecubital vein. In EA, blood samples were obtained regardless of their menstrual phase. Luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol levels were measured. Luteinizing hormone, FSH, and estradiol were analyzed using chemiluminescent immunoassay kit (Abbott Japan Co, Ltd, Tokyo, Japan) with interassay and intra-assay coefficients of variation (CVs) less than 5%.
Anthropometry and Dual-Energy X-Ray Absorptiometry
Body height (m) and body weight (kg) were measured (DC150; TANITA Co, Tokyo, Japan), and body mass index (BMI; kg/m2) was calculated. Bone mineral density of the lumbar spine (L1-L4) was measured by dual-energy x-ray absorptiometry (Discovery DXA System, Hologic, Inc., Marlborough, MA) and analyzed. We defined low BMD as a Z-score ≤−1, which is based on the American College of Sports Medicine guideline.1 Moreover, total fat mass, muscle mass, and %fat were measured by DXA of the whole body. The CV of DXA was 1.0%.
Statistical analysis was performed with JMP11 (SAS Institute, Inc., Tokyo, Japan), and mean ± SD was determined. The correlation factors for low BMD were analyzed by univariable and multivariable logistic regression analysis (forward selection method based on likelihood ratio). Multivariable logistic regression analysis included variables that were significant (P < 0.05) in the univariable logistic regression analysis. In addition, multivariable analysis excluded variables with high collinearity does not apply to a univariable analysis. The BMDs in groups A, B, and C were analyzed using analysis of variance. The level of significance was considered at P < 0.05.
This study was a project of the Japan Sports Agency and was approved by the Ethics Committee of JISS. Written informed consent was obtained from all participants according to the guidelines of the ethics committee of JISS.
Age and Hormone Values
The average age of the participants was 23.6 ± 3.5 years; 23.9 ± 3.7 years in EA; and 22.9 ± 2.7 years in AA. The average hormone levels of EA are shown in Table 2. Estradiol concentrations and LH levels in AA were significantly lower than those in EA (P < 0.001 and P = 0.011, respectively).
The Ratio of Low BMD, Secondary Amenorrhea in Their Teens, and Low BMI in Each Sport Athletes
The ratio of low BMD (Z-score<-1), secondary amenorrhea in their teens, and low BMI (BMI<18.5) of all participants was 18.6% (39/210), 13.8% (29/210), and 18.6% (39/210), respectively. The ratio of low BMD, secondary amenorrhea in their teens, and low BMI of each sport was shown, respectively, in Table 3. In athletics of middle-long distance, was 56.3% (27/48), 47.9% (23/48), and 62.5% (30/48), for soccer, 0% (0/46), 0% (0/46), and 4.3% (2/46), and for other athletic sports, 0% (0/18), 5.6% (1/18), and 11.1% (2/18), respectively.
Correlation Factors for Low BMD
Of the 210 participants, 39 (18.6%) had low BMD. We analyzed the following correlation factors for low BMD by univariable and multivariable logistic regression analysis: secondary amenorrhea for >1 year in their teens, secondary amenorrhea at present, age of menarche, duration of amenorrhea at present, training time (days per week), age they started with their current sports, history of stress fractures, LH, FSH, estradiol, fat mass, muscle mass, body weight, %fat, and BMI.
Univariable logistic regression analysis revealed that the correlation factors for low BMD are secondary amenorrhea for greater than 1 year in their teens [odds ratio (OR), 23.77, 95% confidence interval (CI), 9.21-61.39], secondary amenorrhea at present (OR, 17.02, 95% CI, 7.29-39.75), training time (OR, 2.13, 95% CI, 1.20-3.76), age of menarche (OR, 1.23, 95% CI, 1.02-1.48), duration of amenorrhea at present (OR, 1.08, 95% CI, 1.05-1.11), body weight (OR, 0.85, 95% CI, 0.80-0.90), %fat (OR, 0.82, 95% CI, 0.75-0.90), current estradiol level (OR, 0.82, 95% CI, 0.72-0.94), muscle mass (OR, 0.77, 95% CI, 0.70-0.85), LH (OR, 0.75, 95% CI, 0.64-0.89), fat mass (OR, 0.68, 95% CI, 0.58-0.79), and BMI (OR, 0.45, 95% CI, 0.35-0.58) (Table 4). In the multivariable logistic regression analysis, because body weight, %fat, muscle mass, and fat mass have high collinearity with BMI, these variables were excluded. Multivariable logistic regression analysis showed that secondary amenorrhea in their teens (OR, 7.11, 95% CI, 2.38-21.24; P < 0.001) and BMI at present (OR, 0.56, 95% CI, 0.42-0.73; P < 0.001) were independent correlation factors for low BMD (Table 5).
BMI and BMD at Present in the Lumbar Spine
Data of BMI and BMD in the lumbar at present among all subjects were plotted in Figure 1. A significant positive correlation between BMI and BMD in the lumbar spine was observed (r = 0.574, P < 0.001).
Comparison of BMD of the Athletes With and Those Without Amenorrhea in Their Teens
Twenty-nine athletes had secondary amenorrhea in their teens for greater than 1 year of menstrual deficiency and amenorrhea in their 20s (group A); 29 athletes had regular menstruation in their teens and secondary amenorrhea in their 20s (group B); and 152 athletes had regular menstruation in their teens and 20s (group C). The average Z-score of BMD in groups A, B, and C was −1.56 ± 1.00, −0.45 ± 1.21, and 0.82 ± 1.11 g/cm2, respectively. Group A exhibited significantly lower BMD compared with groups B and C (P < 0.001 and P < 0.001, respectively). Bone mineral density in group B was significantly lower than that in group C (P < 0.001) (Figure 2).
The low BMD ratio (a Z-score of ≤−1) in each group was 72.4% (21/29) in group A, 31.0% (9/29) in group B, and 5.9% (9/152) in group C. The low BMD ratio in group A was significantly higher than that in groups B and C (P < 0.001 and P < 0.001, respectively).
To our knowledge, this is the first study to investigate the correlation factors for low BMD, specifically secondary amenorrhea during teenage years, in female athletes in their 20s. Our study showed that amenorrhea for greater than 1 year during teenage years and low BMI at present are independent correlation factors for low BMD in female athletes. We also found that an athlete with amenorrhea for greater than 1 year during the teenage years is 23 times more likely to develop low BMD in univariable logistic regression analysis. In the multivariable logistic regression analysis, secondary amenorrhea in their teens and BMI at present were independent correlation factors for low BMD. Moreover, when we looked at the actual BMD value, BMD in athletes who had amenorrhea in their teens was lower than that in athletes with regular menstruation in their teens (Figure 2).
In girls, PBM accrual velocity occurs at approximately 11.77 years, whereas more than 25% of adult bone mass is acquired between the ages of 12 and 14 years.17,20–22 Peak bone mass occurs around 20 years of age; thus, the teenage years are a more active period for bone remodeling compared with the 20s.6,23 Bone mineral density is highly influenced by estradiol and loading (body weight) during the teenage years, and normal menstruation during this time is vital for sufficient BMD.4 Our study showed that secondary amenorrhea during teenage years influenced BMD and suggested that the low estradiol levels because of amenorrhea might affect the attainment of PBM.
Furthermore, we also showed that low BMI at present was also a correlation factor for low BMD, and there was positive correlation between BMI and BMD in lumbar spine (Figure 1). Several studies concluded that, in athletes, body weight have a positive correlation with BMD of the lumbar spine, and other studies revealed that low BMD could be improved by gaining body weight.6,23,24 In addition to estradiol value, these reports indicate that loading due to obtaining appropriate body weight is principal factor for increasing BMD. In our study, athletics (middle-long distance) exhibited high frequency of not only a history of amenorrhea in their teens but also low BMI. We demonstrated that appropriate body weight for athletes' height was a significant factor for sufficient BMD, which is supported by the findings of previous studies.25–28 According to our present data, athletes are recommended to gain appropriate BMI to obtain proper BMD.
This study has 3 limitations. First, information on the estradiol levels of the athletes in their teens was not obtained. Nevertheless, the levels could be as low as 24.6 pg/mL, which was observed in AA in their 20s in this study. Hence, an investigation on the relationship between BMD and serum estradiol levels of athletes in their teens is warranted. Second, BMD according to each sport/event was not evaluated dividing into impact and non-impact sports. The BMD of athletes who participate in high-impact sports, such as volleyball, basketball, weightlifting, and jump, is higher than that of athletes who participate in repetitive/non-impact sports, such as swimming and cross-country. Consequently, some athletes in high-impact sports do not have decreased BMD because of mechanical loading regardless of estradiol levels.6,29 In our study, high frequency of low BMD was observed in athletics of middle-long distance. As athletics of middle-long distance were not high-impact sports, further study is needed to investigate BMD divided into high-impact and non-impact sports. Third, our study focused on the BMD of the lumbar spine, which is a representative weight-bearing site. Moreover, further studies are needed to investigate the differences between BMD in weight-bearing and that in non–weight-bearing sites.
In conclusion, we found that in female athletes older than 20 years, secondary amenorrhea in their teens, rather than secondary amenorrhea at present, is a correlation factor for low BMD. To prevent low BMD, secondary amenorrhea screening among female teen athletes is crucial. Moreover, BMD among athletes older than 20 years who had amenorrhea in their teens and teenage athletes with secondary amenorrhea should be evaluated using DXA. Early screening for secondary amenorrhea and low BMI due to low energy availability could prevent low BMD and thus injuries, for example, stress fractures, which consequently influences women health over their lifetime.
The authors thank Kanami Suzuki, Sumi Kawaguchi, Yumiko Sato, Yoko Senzaki for their help with recruiting subjects, and the authors thank Mariko Ogura, Emi Narumi, and Yasuko Iwahara for their technical expertise and Kumiko Saito, Noriyuki Tawara, Tomoko Karita, and Takafumi Onishi for measuring for dual-energy x-ray absorptiometry (DXA).
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