Nancy I. Williams

High prevalence of subtle and severe menstrual disturbances in exercising women: confirmation using daily hormone measures

BACKGROUND The identification of subtle menstrual cycle disturbances requires daily hormone assessments. In contrast, the identification of severe menstrual disturbances, such as amenorrhea and oligomenorrhea, can be established by clinical observation. The primary purpose of this study was to determine the frequency of subtle menstrual disturbances, defined as luteal phase defects (LPD) or anovulation, in exercising women, with menstrual cycles of 26-35 days, who engage in a variety of sports, both recreational and competitive. Secondly, the prevalence of oligomenorrhea and amenorrhea was also determined via measurement of daily urinary ovarian steroids rather than self report alone. METHODS Menstrual status was documented by daily measurements of estrone and pregnanediol glucuronide and luteinizing hormone across two to three consecutive cycles and subsequently categorized as ovulatory (Ovul), LPD, anovulatory (Anov), oligomenorrheic (Oligo) and amenorrheic (Amen) in sedentary (Sed) and exercising (Ex) women. RESULTS Sed (n = 20) and Ex women (n = 67) were of similar (P > 0.05) age (26.3 +/- 0.8 years), weight (59.3 +/- 1.8 kg), body mass index (22.0 +/- 0.6 kg/m2), age of menarche (12.8 +/- 0.3 years) and gynecological maturity (13.4 +/- 0.9 years). The Sed group exercised less (P < 0.001) (96.7 +/- 39.1 versus 457.1 +/- 30.5 min/week) and had a lower peak oxygen uptake (34.4 +/- 1.4 versus 44.3 +/- 0.6 ml/kg/min) than the Ex group. Among the menstrual cycles studied in the Sed group, the prevalence of subtle menstrual disturbances was only 4.2% (2/48); 95.8% (46/48) of the observed menstrual cycles were ovulatory. This finding stands in stark contrast to that observed in the Ex group where only 50% (60/120) of the observed menstrual cycles were ovulatory and as many as 50% (60/120) were abnormal. Of the abnormal cycles in the Ex group, 29.2% (35/120) were classified as LPD (short, inadequate or both) and 20.8% (25/120) were classified as Anov. Among the cycles of Ex women with severe menstrual disturbances, 3.5% (3/86) of the cycles were Oligo and 33.7% (29/86) were Amen. No cycles of Sed women (0/20) displayed either Oligo or Amen. CONCLUSIONS This study suggests that approximately half of exercising women experience subtle menstrual disturbances, i.e. LPD and anovulation, and that one third of exercising women may be amenorrheic. Estimates of the prevalence of subtle menstrual disturbances in exercising women determined by the presence or absence of short or long cycles does not identify these disturbances. In light of known clinical consequences of menstrual disturbances, these findings underscore the lack of reliability of normal menstrual intervals and self report to infer menstrual status.

The presence of both an energy deficiency and estrogen deficiency exacerbate alterations of bone metabolism in exercising women

BACKGROUND Bone loss in amenorrheic athletes has been attributed to energy deficiency-related suppression of bone formation, but not increased resorption despite hypoestrogenism. OBJECTIVE To assess the independent and combined effects of energy deficiency and estrogen deficiency on bone turnover markers in exercising women. DESIGN PINP, osteocalcin, U-CTX-I, TT3, leptin, and ghrelin were measured repeatedly, and bone mineral density (BMD) was measured once in 44 exercising women. Resting energy expenditure (REE) was used to determine energy status (deficient or replete) and was corroborated with measures of metabolic hormones. Daily levels of urinary estrone and pregnanediol glucuronides (E1G, PdG), were assessed to determine menstrual and estrogen status. Volunteers were then retrospectively categorized into 4 groups: 1) Energy Replete+Estrogen Replete (EnR+E2R), (n=22), 2) Energy Replete+Estrogen Deficient (EnR+E2D), (n=7), 3) Energy Deficient+Estrogen Replete (EnD+E2R), (n=7), and 4) Energy Deficient+Estrogen Deficient (EnD+E2D), (n=8). RESULTS The groups were similar (p>0.05) with respect to age (24.05+/-1.75 yrs), weight (57.7+/-2.2 kg), and BMI (21.05+/-0.7 kg/m2). By design, REE/FFM (p=0.028) and REE:pREE (p<0.001) were lower in the EnD vs. EnR group, and the E2D group had a lower REE:pREE (p=0.005) compared to the E2R group. The EnD+E2D group had suppressed PINP (p=0.034), and elevated U-CTX-I (p=0.052) and ghrelin (p=0.028) levels compared to the other groups. These same women also had convincing evidence of energy conservation, including TT3 levels that were 29% lower (p=0.057) and ghrelin levels that were 44% higher (p=0.028) than that observed in the other groups. Energy deficiency was associated with suppressed osteocalcin, and TT3 (p<0.05), whereas estrogen deficiency was associated with decreased E1G (p<0.02), and lower L2-L4 BMD (p=0.033). Leptin was significant in predicting markers of bone formation, but not markers of bone resorption. CONCLUSIONS When the energy status of exercising women was adequate (replete), there were no apparent perturbations of bone formation or resorption, regardless of estrogen status. Estrogen deficiency in exercising women, in the presence of an energy deficiency, was associated with bone loss and involved suppressed bone formation and increased bone resorption. These findings underscore the importance of avoiding energy deficiency, which is associated with hypoestrogenism, to avoid bone health problems.

2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad: 1st International Conference held in San Francisco, California, May 2012 and 2nd International Conference held in Indianapolis, Indiana, May 2013

The Female Athlete Triad is a medical condition often observed in physically active girls and women, and involves three components: (1) low energy availability with or without disordered eating, (2) menstrual dysfunction and (3) low bone mineral density. Female athletes often present with one or more of the three Triad components, and an early intervention is essential to prevent its progression to serious endpoints that include clinical eating disorders, amenorrhoea and osteoporosis. This consensus statement represents a set of recommendations developed following the 1st (San Francisco, California, USA) and 2nd (Indianapolis, Indiana, USA) International Symposia on the Female Athlete Triad. It is intended to provide clinical guidelines for physicians, athletic trainers and other healthcare providers for the screening, diagnosis and treatment of the Female Athlete Triad and to provide clear recommendations for return to play. The 2014 Female Athlete Triad Coalition Consensus Statement on Treatment and Return to Play of the Female Athlete Triad expert panel has proposed a risk stratification point system that takes into account magnitude of risk to assist the physician in decision-making regarding sport participation, clearance and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team and implementation of treatment contracts. This consensus paper has been endorsed by the Female Athlete Triad Coalition, an International Consortium of leading Triad researchers, physicians and other healthcare professionals, the American College of Sports Medicine and the American Medical Society for Sports Medicine.

2014 female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad.

The female athlete triad is a medical condition often observed in physically active girls and women and involves three components: 1) low energy availability with or without disordered eating, 2) menstrual dysfunction, and 3) low bone mineral density. Female athletes often present with one or more of the three triad components, and early intervention is essential to prevent its progression to serious end points that include clinical eating disorders, amenorrhea, and osteoporosis. This consensus statement presents a set of recommendations developed following the first (San Francisco, CA) and second (Indianapolis, IN) International Symposia on the Female Athlete Triad. This consensus statement was intended to provide clinical guidelines for physicians, athletic trainers, and other health care providers for the screening, diagnosis, and treatment of the female athlete triad and to provide clear recommendations for return to play. The expert panel has proposed a risk stratification point system that takes into account magnitude of risk to assist the physician in decision making regarding sport participation, clearance, and return to play. Guidelines are offered for clearance categories, management by a multidisciplinary team, and implementation of treatment contracts.

Higher Incidence of Bone Stress Injuries With Increasing Female Athlete Triad–Related Risk Factors: A Prospective Multisite Study of Exercising Girls and Women

Background: Identifying the risk factors associated with a bone stress injury (BSI), including stress reactions and stress fractures, may aid in targeting those at increased risk and in formulating prevention guidelines for exercising girls and women. Purpose: To evaluate the effect of single or combined risk factors as defined by the female athlete triad—a syndrome involving 3 interrelated spectrums consisting of energy availability, menstrual function, and bone mass—with the incidence of BSIs in a multicenter prospective sample of 4 cohorts of physically active girls and women. Study Design: Cohort study; Level of evidence, 3. Methods: At baseline, participants’ (N = 259; mean age, 18.1 ± 0.3 years) anthropometric characteristics, eating attitudes and behaviors, menstrual function, sports participation or exercise activity, and pathological weight control behaviors were assessed. Dual-energy x-ray absorptiometry (DXA) measured the bone mass of the whole body, total hip, femoral neck, lumbar spine, and body composition. Participants were followed prospectively for the occurrence of injuries; those injuries confirmed by a physician were recorded. Results: Twenty-eight participants (10.8%) incurred a BSI. Forty-six percent of those who had ≥12 h/wk of purposeful exercise, a bone mineral density (BMD) Z score <–1.0, and who exhibited 3 to 4 of the following: BMI <21.0 kg/m2, oligo- or amenorrhea, elevated dietary restraint, and/or participation in a leanness sport exercise/activity at baseline, incurred a BSI during the prospective study period. Single factors significantly (P < .05) associated with the development of a BSI included ≥12 h/wk of purposeful exercise (14.7%), BMI <21.0 kg/m2 (15.3%), and low bone mass (BMD Z score <–1.0; 21.0%). The strongest 2- and 3-variable combined risk factors were low BMD (Z score <–1.0) + ≥12 h/wk of exercise, with 29.7% incurring a BSI (odds ratio [OR], 5.1; 95% CI, 2.2-12.1), and ≥12 h/wk of exercise + leanness sport/activity + dietary restraint, with 46.2% incurring a BSI (OR, 8.7; 95% CI, 2.7-28.3). Conclusion: In the sample, which included female adolescents and young adults participating in competitive or recreational exercise activities, the risk of BSIs increased from approximately 15% to 20% for significant single risk factors to 30% to 50% for significant combined female athlete triad–related risk factor variables. These data support the notion that the cumulative risk for BSIs increases as the number of Triad-related risk factors accumulates.

Maturation time of new granule cells in the dentate gyrus of adult macaque monkeys exceeds six months

We studied two groups of adult macaque monkeys to determine the time course of adult neurogenesis in the dentate gyrus of the hippocampus. In the first group, six adult monkeys (Macaca mulatta) received a single injection of the thymidine analog BrdU (75 mg/kg), which is incorporated into replicating DNA and serves as a marker for new cell birth. Brain tissue was collected 48 h, 2 wk, and 6 wk after BrdU injection to examine the initial stages of neurogenesis. Because mature neurons were not evident at 6 wk, we examined tissue collected over a longer time course in a second study. In this study, eight monkeys (Macaca fascicularis) who were subjects in a separate exercise study received 10 weekly injections of BrdU (75 mg/kg), and brain tissue was collected at 16 and 28 wk from the first injection. Based on the timing of expression of neuronal cell markers (βIII-tubulin, doublecortin, NeuN), the extent of dendritic arborization, and acquisition of mature cell body morphology, we show that granule cell maturation in the dentate gyrus of a nonhuman primate is protracted over a minimum of a 6-mo time period, more than 6 times longer than in rodents. The lengthened time course for new cell maturation in nonhuman primates may be appropriate for preservation of neural plasticity over their longer life span and is relevant to our understanding of antidepressant and other therapies that have been linked to neurogenesis in humans.

Prevalence of individual and combined components of the female athlete triad.

PURPOSE The female athlete triad (Triad) is a syndrome linking low energy availability (EA) with or without disordered eating (DE), menstrual disturbances (MD), and low bone mineral density (BMD) in exercising women. The prevalence of Triad conditions (both clinical and subclinical) has not been clearly established.The purpose of this review is to evaluate the studies that determined the prevalence of clinical or subclinical Triad conditions (low EA, DE, MD, and low BMD) in exercising women and in women participating in lean (LS) versus nonlean sports (NLS) using self-report and/or objective measures. METHODS A review of publications using MEDLINE and PubMed was completed. Randomized controlled trials and observational studies that evaluated the prevalence of clinical and subclinical Triad conditions (MD, low BMD, low EA, and DE) in exercising women were included. RESULTS Sixty-five studies were identified for inclusion in this review (n = 10,498, age = 21.8 ± 3.5 yr, body mass index = 20.8 ± 2.6 kg·m; mean ± SD). A relatively small percentage of athletes (0%-15.9%) exhibited all three Triad conditions (nine studies, n = 991). The prevalence of any two or any one of the Triad conditions in these studies ranged from 2.7% to 27.0% and from 16.0% to 60.0%, respectively. The prevalence of all three Triad conditions in LS athletes versus NLS athletes ranged from 1.5% to 6.7% and from 0% to 2.0%, respectively. LS athletes demonstrated higher prevalence rates of MD and low BMD (3.3% vs 1.0%), MD and DE (6.8%-57.8% vs 5.4%-13.5%), and low BMD and DE (5.6% vs 1.0%) than the NLS athletes. CONCLUSIONS Although the prevalence of individual/combined Triad conditions is concerning, our review demonstrates that additional research on the prevalence of the Triad using objective and/or self-report/field measures is necessary to more accurately describe the extent of the problem.

Strenuous exercise with caloric restriction: effect on luteinizing hormone secretion.

To test whether strenuous exercise with and without caloric restriction alters LH secretion, and whether these changes are apparent in the immediate post-exercise period, LH pulse parameters were studied in four moderately trained eumenorrheic women over three successive menstrual cycles. Blood samples were obtained 5 h before and 5 h after 90 min of running at 74% VO2max. Each test was preceded by a 7-d treatment of controlled diet and exercise (74% VO2max). During CONTROL, subjects were eucaloric on days 1-7, and performed no exercise on days 5-7. During STTI (short-term training increase), subjects were eucaloric and completed 90 min runs on days 5-7. During DIET/STTI, subjects consumed 60% of the calories necessary to maintain weight on days 1-7, and exercised as in STTI. A significant decrease in overall (0700-1830 h) LH pulse frequency during DIET/STTI compared with CONTROL and STTI treatments was observed. No changes were found in mean serum LH levels or peak amplitude. These results suggest that high-volume training combined with caloric restriction may predispose one to exercise-induced changes in LH pulse frequency, while adequate caloric intake may prevent these changes.

The effects of metformin with lifestyle therapy in polycystic ovary syndrome: a randomized double-blind study

OBJECTIVE To determine if the combination of lifestyle (caloric restriction and exercise) and metformin (MET) would be superior to lifestyle and placebo (PBO) in improving the polycystic ovary syndrome (PCOS) phenotype. DESIGN Double-blind randomized 6-month trial of MET versus PBO. SETTING Two academic medical centers. PATIENT(S) One hundred fourteen subjects with PCOS were randomized to MET (N = 55) or PBO (N = 59). INTERVENTION(S) Subjects collected urine daily for ovulation monitoring, had monthly monitoring of hormones and weight and determination of body composition by dual-energy x-ray absorptiometry, glucose tolerance, and were evaluated for quality of life at baseline and completion. MAIN OUTCOME MEASURE(S) Ovulation rates and testosterone levels. RESULT(S) Dropout rates were high. There was no significant difference in ovulation rates. Testosterone levels were significantly lower compared with baseline in the MET group at 3 mos but not at 6 mos. There were no differences in weight loss between groups, but MET showed a significant decline at 6 months compared with baseline (-3.4 kg, 95% confidence interval -5.3 to -1.5 kg). We noted divergent effects of MET versus PBO on oral glucose tolerance test indices of insulin sensitivity (increased) and secretion (worsened). Total bone mineral density increased significantly in MET. There were no differences in quality of life measures between the groups. The MET group had increased diarrhea and headache, but fewer bladder infections and musculoskeletal complaints. CONCLUSION(S) The addition of metformin to lifestyle therapy produced little reproductive or glycemic benefit in women with PCOS, although our study had limited power owing to a high dropout rate. It is not possible at baseline to identify women likely to drop out.

Neuromuscular performance and knee laxity do not change across the menstrual cycle in female athletes

Female athletes incur anterior cruciate ligament ruptures at a rate at least twice that of male athletes. Hypothesized factors for the increased injury risk in females include biomechanical, neuromuscular, and hormonal differences between genders. A wealth of literature exists examining these potential predispositions individually, but the interactions between these factors have not been examined extensively. Our purpose was to investigate changes in neuromuscular control and laxity at the knee across the menstrual cycle of healthy females. Fourteen female collegiate athletes with normal, documented ovulatory menstrual cycles, confirmed ovulation, and no history of serious knee injury participated. The presence and timing of ovulation was determined during a screening cycle with ovulation detection kits and during an experimental cycle with collection of daily urine samples and subsequent analysis of urinary estrone-3-glucuronide (E3G) and pregnanediol-3-glucoronide (PdG), which correlate with circulating estrogen and progesterone. Each subject had measures of knee neuromuscular performance and laxity once during the mid-follicular, ovulatory, and mid-luteal stages of her menstrual cycle. The test battery included assessments of knee flexion and extension peak torque, passive knee joint position sense, and postural control in single leg stance. Knee joint laxity was measured with an arthrometer. Analyses of variance revealed that E3G and PdG levels were significantly different across the three testing sessions, but there were no significant differences in the measures of strength, joint position sense, postural control, or laxity. No significant correlations were found between changes in E3G or PdG levels and changes in the performance and laxity measures between sessions. These results suggest that neuromuscular control and knee joint laxity do not change substantially across the menstrual cycle of females despite varying estrogen and progesterone levels.