Exercise-associated Menstrual Disturbances Research Articles

12-months of increased dietary intake does not exacerbate disordered eating-related attitudes, stress, or depressive symptoms in women with exercise-associated menstrual disturbances: The REFUEL randomized controlled trial

Disordered eating-related attitudes are a leading cause of energy deficiency and menstrual disturbances in exercising women. Although treatment recommendations include psychological counseling with increases in dietary intake, a key concern is whether increased dietary intake may exacerbate negative eating behaviors. ObjectiveTo determine the effects of a 12-month nutritional intervention on eating-related attitudes and psychological characteristics in exercising women with oligomenorrhea/amenorrhea (Oligo/Amen). MethodsIntent-to-treat analysis of the REFUEL randomized controlled trial (#NCT00392873) in 113 exercising women (age [mean±SEM]:] 21.9 ± 0.4 yrs; BMI: 20.9 ± 0.2 kg/m2). Women were randomized to increase energy intake 20–40% above baseline energy needs (Oligo/Amen+Cal, n = 40) or maintain energy intake (Oligo/Amen Control, n = 36) while maintaining their exercise behaviors. A reference group of ovulatory women (OVref, n = 37) maintained diet and exercise behaviors. Body composition, eating attitudes, stress, and depressive symptoms were assessed at baseline and every 3 months. ResultsAt baseline, the Oligo/Amen groups had higher drive for thinness, cognitive restraint, and eating disorder risk than OVref group (p < 0.001). Increased energy intake led to increases in percent body fat and fat mass (p < 0.010), but not psychobehavioral outcomes, in the Oligo/Amen+Cal compared to Oligo/Amen Control group. Independent of group, cognitive restraint decreased (p < 0.001) and resilient coping increased (p < 0.007) over 12-months, while perceived stress (p = 0.143) and depressive symptoms (p = 0.344) were unchanged. DiscussionLong-term nutritional intervention consisting of modest increases in dietary intake with guidance from a registered dietician and a psychologist increases body and fat mass without increasing disordered eating-related attitudes, stress, or depressive symptoms in exercising women with Oligo/Amen.

Impaired vascular function in exercising anovulatory premenopausal women is associated with low bone mineral density.

In estrogen-deficient post-menopausal women, osteoporosis shares a common link with cardiovascular disease risk, including endothelial dysfunction. The current study sought to examine associations between bone mineral density (BMD) and endothelial function in estrogen-deficient premenopausal women with exercise-associated menstrual disturbances. Recreationally trained women (24.3±0.8years; overall mean±SEM) who were estrogen deficient (amenorrheic or eumenorrheic anovulatory cycles; E2Def; n=13) or estrogen replete (eumenorrheic ovulatory cycles; E2Rep; n=14) were studied. Total body and lumbar BMD (L1-L4) were determined using dual-energy X-ray absorptiometry. Serum markers of oxidative stress (oxidized low-density lipoprotein; OxLDL), energy deficiency (triiodothyronine), and bone turnover (osteocalcin, c-telopeptide X, P1NP) were assessed. Estrogen exposure was determined by assessing daily urinary estrone-3-glucuronide (E1G) across a monitoring period. Calf blood flow (CBF), an index of endothelial function, was measured using strain-gauge plethysmography. CBF, total body and L1-L4 BMD, triiodothyronine and E1G were lower (P<0.05), and c-telopeptide crosslinks higher (P<0.05) in E2Def. Osteocalcin and OxLDL did not differ (P>0.05) between groups. L1-L4 BMD, osteocalcin, and E1G were the strongest predictors of CBF (R2 =0.615, P<0.001). CBF was the strongest predictor of L1-L4 BMD (R2 =0.478, P<0.001). L1-L4 (r=0.558, P=0.008) and CBF (r=0.534, P=0.004) were independently correlated with E1G. In young recreationally trained premenopausal women with anovulatory menstrual disturbances, low CBF predicts decreased lumbar BMD, suggesting impaired peripheral endothelial function may predict early unfavorable changes in bone metabolism. This finding may be of relevance in the early detection of cardiovascular and bone health decrements in otherwise healthy estrogen-deficient premenopausal women.

Rationale and study design of an intervention of increased energy intake in women with exercise-associated menstrual disturbances to improve menstrual function and bone health: The REFUEL study.

PurposeExercising women who consume inadequate energy relative to expenditure are at risk for downstream health consequences, such as menstrual cycle disturbances and poor bone health. Collectively, these conditions are known as the Female Athlete Triad (Triad). Clinicians often prescribe hormonal contraceptives to address this issue; however, the recommended treatment is reversal of the energy deficit. This paper describes the design of the REFUEL study, a randomized controlled trial (RCT) that explored the effectiveness of a 12-month intervention of increased energy intake on the reversal of an unhealthy energetic status and menstrual dysfunction and subsequent improvements in bone health in exercising women with severe menstrual cycle disturbances.MethodsWomen between the ages of 18–35 years and participating in at least 2 h/week of purposeful exercise were recruited. Those who reported irregular or absent menstrual cycles and were determined to have an exercise-associated menstrual disturbance (EAMD) were randomized into either the treatment group (EAMD + Cal), which was instructed to increase caloric intake throughout the intervention, or a control group (EAMD Control). Women who reported eumenorrhea were eligible for the ovulatory (OV) Control group. Repeated measures of energetic and metabolic status, reproductive status, and skeletal health were obtained.DiscussionThe REFUEL study is the first RCT to explore a non-pharmacological treatment approach among exercising women with the Triad. 118 women were randomized, and 55 women completed the entire study. The findings of this study have the potential to inform and alter clinical practice for exercising young women who present with this condition.

Reductions in urinary collection frequency for assessment of reproductive hormones provide physiologically representative exposure and mean concentrations when compared with daily collection.

To determine if reducing the frequency of urinary sample collection from daily to 5, 3, or 2 days per week during a menstrual cycle or 28-day amenorrheic monitoring period provide accurate representations of the reproductive hormone metabolites estrone-1-glucuronide (E1G) and pregnanediol glucuronide (PdG) exposure and mean concentrations. Exercising women presenting with eumenorrhea or exercise-associated menstrual disturbances collected daily urine samples for the assessment of E1G and PdG concentrations. After enzyme immunoassay analysis of the daily samples, E1G and PdG data were systematically removed from each menstrual cycle or amenorrheic monitoring period to mimic three reduced collection frequencies, representing 5, 3, and 2 days per week. Exposure and mean concentration were calculated for both hormones and all four urinary collection frequencies. E1G and PdG exposure and mean cycle concentrations derived from reduced collection frequencies were not different from daily collection (P > 0.05), independent of whether menstrual cycles and monitoring periods were analyzed together or separately. Bland-Altman analysis indicated acceptable agreement between each reduced collection frequency and daily collection. Compared with daily urinary collection, a reduced collection frequency of 5, 3, or 2 days each week provides accurate E1G and PdG profiles of collection periods of various lengths and types of menstrual function. Reduction of urinary sample collection frequency may enable researchers to reduce participant burden and costs, increase compliance, and study a wider range of study populations.

Elevated PYY is Associated with Low Energy Dense Diets in Women with Exercise-Associated Menstrual Disturbances

Low energy dense diets are associated with weight loss, presumably due to greater satiety coincident with low energy intake (EI). Low EI relative to energy expenditure (EE) and high cognitive restraint (CR) are associated with exercise associated menstrual disturbances. We previously documented that women with exercise-associated amenorrhea exhibit lower energy dense diets when compared to ovulatory exercising women. We wished to determine whether the maintenance of lower kcal diets may also include a biological component. PURPOSE: To test the hypothesis that low energy dense diets are associated with elevated fasting PYY, an anorexic gut peptide, and or decreased ghrelin (Ghr), an orexigenic gut peptide, and higher CR in women with exercise associated amenorrhea. METHODS: Subjects included 12 exercising women with amenorrhea (AM) and 12 exercising ovulatory women (OV). A blood sample for endocrine/metabolic hormones, a physical exam, and self reported menstrual history in addition to measurements of urinary estrone-1-glucuronide, pregnanediol-3-glucuronide, and LH over 1 menstrual cycle were used to confirm exercise associated functional hypothalamic amenorrhea or ovulatory menstrual status. EI was determined with 3-day diet logs. Energy Density (ED; kcals/g) was determined with and without beverages (bev). Indices of EE included resting metabolic rate (RMR, kcals/day), expenditure from purposeful exercise (kcals/day) and energy availability (EA; (EI kcals- exercise kcals)/kgFFM). Fasting blood samples were obtained for analysis of fasting total PYY and Ghr. The Three-Factor Eating Questionnaire (TFEQ) was used to measure CR. RESULTS: Subjects were ages 18-35 yrs with a BMI of 20.88 ± 1.23 kg/m2, %body fat of 23.60 ± 4.29 and 13.62 ± 3.05 kg body fat. Independent t-tests showed that body weight (kg), RMR (kcals/day), EI, and EA (kcals/kgFFM) were significantly lower in AM subjects (p<0.05) with a trend toward significantly lower % body fat (p=0.10). ED in AM was significantly lower vs. OV subjects (p=0.02) when bev were included. CR (p=0.002) and PYY (p=0.006) were also significantly higher in the AM subjects. No significant differences were found for Ghr (p=0.53). CONCLUSION: Elevated PYY in addition to high CR may allow for low EI as a result of low energy dense diets in women with exercise associated AM.

Oligomenorrhoea in Exercising Women

To date, the predominant mechanism underlying menstrual disturbances in exercising women supports an underlying energy deficiency-related aetiology, in which a failure to compensate dietary intake for the energy cost of exercise suppresses reproductive function. Increasing evidence demonstrates that energy deficiency plays a causal role in the induction of amenorrhoea in exercising women, and consistent with this mechanism are findings of glucoregulatory perturbations such as low triiodothyronine, reduced insulin secretion and elevated cortisol, growth hormone and ghrelin levels. The menstrual disturbance that may differ in its energetic characteristics and, perhaps in its androgenic and ovarian steroid environment, is oligomenorrhoea. We conducted a systematic review of the literature to begin to understand whether oligomenorrhoea in exercising women is a mild subclinical phenotype of polycystic ovarian syndrome (PCOS) in which exercise is conferring beneficial effects in protecting women from the classic PCOS phenotype, or whether oligomenorrhoea is part of the spectrum of menstrual disturbances caused by an energy deficiency that is often reported in exercising women with menstrual disturbances. We included observational, randomized controlled trials and cross-sectional studies that reported clinical, hormonal and metabolic profiles in exercising women with amenorrhoea or oligomenorrhoea and in women with PCOS. Previous studies examining the underlying mechanisms and consequences of exercise-associated menstrual disturbances have grouped exercising amenorrhoeic and oligomenorrhoeic women into a single group, and have relied primarily on self-reported menstrual history. Although scarce, the data available to date suggest that hyperandrogenism, such as that observed in PCOS, may likely be associated with oligomenorrhoea in exercising women, and may not always represent hypothalamic inhibition secondary to an energy deficiency. It is critical to closely examine the metabolic and endocrine status of women with menstrual disturbances because the treatment strategies for energy deficiency-related menstrual disturbances differ from that of disturbances traceable to hyperandrogenaemia. Further investigation is necessary to explore whether different endocrine aetiologies underly menstrual disturbances, particularly oligomenorrhoea, in physically active women.

Short-term response of bone turnover to low-dose oral contraceptives in exercising women with hypothalamic amenorrhea

Background We examined the response of bone turnover markers and indices of energy status after 2 weeks of oral contraceptive (OC) therapy in premenopausal women with exercise-associated menstrual disturbances (EAMD). Study Design Six women with EAMD received one 28-day cycle of a triphasic OC containing 180–250 mcg norgestimate/25 mcg ethinyl estradiol (EAMD+OC) and six were controls (EAMD controls). Bone turnover markers amino-terminal propeptide of Type I procollagen and serum carboxy-terminal telopeptides of Type I collagen (PINP and SCTX-I) were assessed at baseline and after 2 weeks of OC therapy (EAMD+OC) or after a 30-day monitoring period (EAMD controls). Total triiodothyronine, resting energy expenditure (REE) and dietary intake were assessed as secondary end points. The absolute and percent changes from baseline in the primary and secondary outcomes were evaluated using an analysis of covariance, adjusting for baseline values of the corresponding outcome. Results Compared to EAMD controls, a significant change from baseline was observed in the EAMD+OC group for PINP (mean±SEM, 9.9±6.1 vs. −33.9±9.0 mcg/L; p=.005) and SCTX-I (−0.02±0.11 vs. −0.25±0.07 ng/mL; p=.017), but not osteoprotegerin (−0.53±0.22 vs. 0.20±0.44 pmol/L; p=.429) after 2 weeks (14.7±0.3 days) of OC therapy. Total triiodothyronine levels were elevated in the EAMD+OC group after therapy compared with EAMD controls (19.7±4.1 vs. −8.4±4.9 ng/dL; p=.002); however, no differences between groups were observed for the changes in REE or dietary intake. Conclusion Our data demonstrate that 2 weeks of low-dose OC therapy rapidly reduced markers of bone resorption and formation, without any significant impact on energy status in women with EAMD.

Dietary Cognitive Restraint

0219 Dietary cognitive restraint (CR) describes a conscious limitation of food intake in an effort to control body weight. Higher levels of CR have been reported in exercising women with exercise-associated menstrual disturbances (EAMD) when compared to levels in eumenorrheic (EU) active women. PURPOSE: To determine if dietary CR also serves as a marker for altered energy homeostasis in EAMD, since EAMD is also linked to physiological energy conserving adaptations. METHODS: Athletic women of varying activity levels (n = 38) completed the three factor eating questionnaire and the EDI2, and blood samples were obtained during the early follicular phase (days 2–6) of two consecutive menstrual cycles in EU athletes or day 1 of two consecutive 30-day periods in oligo/amenorrheic (O/Amen) athletes. Blood samples for each cycle were assayed for total triiodothyronine (TT3), insulin and leptin and levels for each cycle averaged for each subject. RESULTS: In this study, 18 athletes exhibited high CR (above the cut-off for normal, i.e. > 10), as defined in the original questionnaire, and 20 athletes demonstrated CR scores in the normal range. These groups were similar (p>0.05) with respect to age (24.6±0.8 yrs), height (164.2±9.5 cm), weight (57.3±1.1 kg), percent body fat (22.9±1.0), age of menarche (12.6±0.2 yrs) and VO2 max (44.2±0.9 ml/kg/min). The athletes with high CR (n = 18) had a higher (p<0.001) mean score of 14.3±0.7 compared to the non-CR group (n = 20) who had a mean score of 4.8±0.5. The high CR group also had a higher (p = 0.035) score on the EDI-2 subscale of drive for thinness than the non-CR group, 5.0±1.2 and 1.9±0.8, respectively. TT3 levels were lower (p = 0.023) in the high CR group (1.4±0.08 nmol/L) compared to the non-CR group (1.6±0.08 nmol/L). Insulin levels were lower (p = 0.048) in the high CR group (27.78±2.1 pmol/L) compared to the non-CR group (38.9±4.2 pmol/L). Leptin levels were similar (4.8±1.1 ng/ml, p = 0.28), likely due to similar fat mass (12.7±0.7 g) between the groups. Among the high CR group, 50% had either O/Amen (n = 9/18), whereas, among the non-CR group, 25% had either O/Amen (n = 5/20), demonstrating that high CR was dependent on menstrual status (χ2 = 9.9, p = 0.042). CONCLUSION: These data suggest that high CR is associated with markers of altered energy homeostasis indicating low energy availability, including TT3 and insulin, previously demonstrated to be low in athletic women with EAMD and that menstrual status was associated with high CR. Funded by Arthur Thornton Cardiopulmonary Fund.

Dietary Cognitive Restraint

0219 Dietary cognitive restraint (CR) describes a conscious limitation of food intake in an effort to control body weight. Higher levels of CR have been reported in exercising women with exercise-associated menstrual disturbances (EAMD) when compared to levels in eumenorrheic (EU) active women. PURPOSE: To determine if dietary CR also serves as a marker for altered energy homeostasis in EAMD, since EAMD is also linked to physiological energy conserving adaptations. METHODS: Athletic women of varying activity levels (n = 38) completed the three factor eating questionnaire and the EDI2, and blood samples were obtained during the early follicular phase (days 2–6) of two consecutive menstrual cycles in EU athletes or day 1 of two consecutive 30-day periods in oligo/amenorrheic (O/Amen) athletes. Blood samples for each cycle were assayed for total triiodothyronine (TT3), insulin and leptin and levels for each cycle averaged for each subject. RESULTS: In this study, 18 athletes exhibited high CR (above the cut-off for normal, i.e. > 10), as defined in the original questionnaire, and 20 athletes demonstrated CR scores in the normal range. These groups were similar (p>0.05) with respect to age (24.6±0.8 yrs), height (164.2±9.5 cm), weight (57.3±1.1 kg), percent body fat (22.9±1.0), age of menarche (12.6±0.2 yrs) and VO2 max (44.2±0.9 ml/kg/min). The athletes with high CR (n = 18) had a higher (p<0.001) mean score of 14.3±0.7 compared to the non-CR group (n = 20) who had a mean score of 4.8±0.5. The high CR group also had a higher (p = 0.035) score on the EDI-2 subscale of drive for thinness than the non-CR group, 5.0±1.2 and 1.9±0.8, respectively. TT3 levels were lower (p = 0.023) in the high CR group (1.4±0.08 nmol/L) compared to the non-CR group (1.6±0.08 nmol/L). Insulin levels were lower (p = 0.048) in the high CR group (27.78±2.1 pmol/L) compared to the non-CR group (38.9±4.2 pmol/L). Leptin levels were similar (4.8±1.1 ng/ml, p = 0.28), likely due to similar fat mass (12.7±0.7 g) between the groups. Among the high CR group, 50% had either O/Amen (n = 9/18), whereas, among the non-CR group, 25% had either O/Amen (n = 5/20), demonstrating that high CR was dependent on menstrual status (χ2 = 9.9, p = 0.042). CONCLUSION: These data suggest that high CR is associated with markers of altered energy homeostasis indicating low energy availability, including TT3 and insulin, previously demonstrated to be low in athletic women with EAMD and that menstrual status was associated with high CR. Funded by Arthur Thornton Cardiopulmonary Fund.

Development of Exercise-Associated Menstrual Disturbances

Development of Exercise-Associated Menstrual Disturbances

Development of Exercise-Associated Menstrual Disturbances

Development of Exercise-Associated Menstrual Disturbances

Fasting Ghrelin Levels in Physically Active Women

1915 Ghrelin is a peripheral metabolic signal of energy status involved with the regulation of hunger, food intake, body weight, and energy balance. While recent evidence supports a potential physiological role of ghrelin in reproductive function, the relationship of ghrelin to exercise-associated menstrual disturbances and other endocrine adaptations to low energy availability has not been evaluated. PURPOSE: To test whether differences in fasting ghrelin levels exist in exercising women exhibiting alterations in metabolic status and menstrual cycle abnormalities. METHODS: Menstrual cycle status, defined as ovulatory, luteal phase deficient (LPD), anovulatory, or amenorrheic, was determined through daily urine collections examining estrone conjugates (E1C), pregnanediol-3-glucuronide (PdG), and luteinizing hormone (LH) for two to three consecutive cycles or equivalent time periods in 10 sedentary and 30 moderately active women. Both groups were matched for age (27.7 1.2 yrs), body mass (60.2 3.3 kg), menstrual cycle length (28.4 0.9 days), and reproductive age (14.4 1.2 yrs). A blood sample was collected once during the follicular phase of each menstrual cycle or on an arbitrary day in amenorrheic subjects and analyzed for total ghrelin, insulin, total T3, and leptin concentrations. Each subject was classified according to individual exercise status and the predominant menstrual cycle status displayed in at least two of the three, or two of the two, menstrual cycles evaluated. This classification resulted in 10 sedentary ovulatory subjects (SedOvul), 11 exercise ovulatory subjects (ExOvul), 11 exercise LPD or anovulatory subjects (ExLPD/ANOV), and 8 exercise amenorrheic (ExAmen) subjects. RESULTS: Ghrelin was significantly elevated in the ExAmen category (723.7 ± 40.8 pmol/L) when compared to all other categories (p<0.001), SedOvul (392.8 ± 32.0 pmol/L), ExOvul (418.0 ± 34.6 pmol/L), and ExLPD/Anov (380.4 ± 31.4 pmol/L). Leptin levels were lower in all groups versus SedOvul (P <0.001), while insulin was lower in both ExLPD/Anov and ExAmen categories versus SedOvul and ExOvul (p<0.018). Total T3 was lower in ExAmen compared to all other groups (P<0.001) with concentrations in ExLPD/Anov and ExOvul exceeding those in SedOvul (p<0.05). CONCLUSION: These data indicate a metabolic hormonal profile consistent with low energy availability in exercising women across a range of menstrual abnormalities. This study also introduces ghrelin as a potential additional indicator of energy status that uniquely discriminates amenorrheic athletes from athletes with other more subtle menstrual disturbances.